clinical trial protocol
exclusion criteria

Patients who meet any of the criteria cannot be enrolled in this study:
(1) Use of systemic immunosuppressive or systemic cortisol (≥10 mg prednisone or other equivalent hormone) within 4 weeks prior to the first dose.  
(2) Prior use of selective FGFR4 inhibitor and/or pan-FGFR inhibitor therapy. (3) Use of cytotoxic chemotherapeutics within 4 weeks prior to the first dose, OR use of state-approved Chinese traditional patent drugs/Chinese traditional drugs with an antitumor effect within 2 weeks prior to the first dose. Note: For mitomycin C or nitrosoureas, 6-week washout is required; for small molecule targeted drugs and oral fluorouracil drugs, a washout period of 2 weeks or five T1/2 of the drug (whichever is longer) is required.  
(4) Anti-tumor endocrine therapy, radiotherapy, interventional embolization, radiofrequency, proton therapy, radioimmunotherapy, immunotherapy or other biotherapies within 4 weeks prior to the first dose (if five T1/2 of the drug/therapy used by the patient is confirmed to be <4 weeks, five T1/2 shall prevail).  
(5) Use of other clinical investigational drug or therapy that not marketed within 4 weeks prior to the first dose.  
(6) Patient is receiving drugs or therapies prohibited in the protocol (e.g., strong CYP3A4 inhibitors, strong CYP3A4 inducers, strong CYP3A5 inhibitors, strong CYP3A5 inducers, sensitive CYP3A4 substrates with a narrow therapeutic index, sensitive CYP2B6 substrates with a narrow therapeutic range, etc., see Section 6.2 of the main text for details)
and cannot discontinue such use at least 2 weeks prior to the first dose or throughout the study.  
(7) Pregnant or lactating females. (8) Patient with known hypersensitivity to any ingredient of BB102 tablets, or patient who have a history of drug allergy and is judged as not suitable for participating in this study by the investigator.  
(9) Presence of clinically significant gastrointestinal disorder that may affect the intake, transport or absorption of the study drug (e.g., dysphagia, uncontrollable nausea and vomiting, active gastric ulcer, ulcerative colitis, Crohn's disease, chronic diarrhea, intestinal obstruction, and other conditions determined by the investigator that may cause gastrointestinal bleeding, perforation, etc.) at screening.  
(10) Patient with concurrent cancer (adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease recurrence, except carcinoma in situ) within 5 years prior to the first dose.  
(11) Adverse reaction of the prior anti-tumor therapy not yet recovered to grade ≤1 as assessed by CTCAE v5.0 at screening (except the toxicities that are judged as having no safety risk by the investigator, such as alopecia, asthenia, GGT increased, ALP increased, grade 2 peripheral neurotoxicity, thyroid function decreased stabilized by hormone replacement therapy, etc.).  
(12) Clinically uncontrollable third space effusion at screening, which, at the investigator's discretion, is not suitable for enrollment. Note: For patients with third space effusion (pleural ascites, pericardial effusion) who are stable after local drainage and drug infusion, and drug-eluted for at least five T1/2 or 14 days (whichever is shorter), they can be considered for enrollment.  
(13) Presence of clinically symptomatic metastases to central nervous system or meninges or other evidence showing that metastatic lesions in central nervous system or meninges have not yet been controlled at screening, which, at the investigator's discretion, is not suitable for enrollment. Note: Patients with central nervous system metastases or meningeal metastases who are asymptomatic or in a stable state after treatment before the first dose can be considered for enrollment.  
(14) History of severe neurological or psychiatric disorders, including epilepsy, dementia, or moderate to severe depression, etc.  
(15) History of drug abuse or dependence. (16) Clinically significant and uncontrolled cardiovascular diseases, including:
➢ Serious cardiac rhythm or conduction abnormality at screening, such as ventricular arrhythmia that requires clinical intervention, second/third-degree AV block, etc.;
➢ Myocardial infarction within 12 months prior to the first dose;
➢ Acute coronary syndrome, congestive cardiac failure, aortic dissection, cerebral stroke or other grade ≥3 cardiovascular and cerebrovascular events within 6 months prior to the first dose;
➢ Arterial or deep venous thrombosis within 6 months prior to the first dose, or those who need to monitor international normalized ratios or use anticoagulants at screening. Note: Patients with superficial venous thrombosis which do not need treatment can be considered for enrollment; patients who can stop anticoagulant within 2 weeks before the first dose and during the administration period can be considered for enrollment;
➢ Mean resting QTcF >480 ms at screening, which are obtained from three 12-lead electrocardiograms (ECGs) [Note: QTcF is calculated based on Fridericia formula, QTcF = QT/(RR^0.33)];
➢ Heart failure of New York Heart Association Class ≥II at screening;  
| ➢               | Left ventricular ejection fraction (LVEF) <50% at screening;                                                                                             |
|-----------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|
| ➢               | Hypertension (defined as systolic blood pressure ≥160 mmHg or diastolic blood  pressure ≥100 mmHg) that medication fails to control stably at screening; |
| ➢               | Hyperglycemia that medication fails to control stably at screening.                                                                                      |
| (17)            | Pulmonary embolism within 6 months prior to the first dose, or interstitial pneumonia                                                                    |
| at screening. (18) Prior allogeneic stem cell transplantation, bone marrow transplantation or vital organ  transplantation. (19) Surgical operation (excluding aspiration biopsy) of vital organs or significant trauma  within 8 weeks prior to the first dose, or unrecovered surgical effect at screening, or  planned elective major surgery during the study period. (20) Presence of uncontrollable infectious disease, congenital immunodeficiency disease,  acquired immunodeficiency syndrome [positive for human immunodeficiency virus  antibody (HIV-Ab)], syphilis (positive for syphilis antibody), active hepatitis B [for nonHCC patients, hepatitis B virus (HBV)-DNA >500 IU/mL; for HCC patients, HBVDNA >104 copies/mL or 2000 IU/mL; hepatitis B patients need to take oral anti-HBV drugs regularly during the administration of BB102 tablets], hepatitis C virus (HCV) infection (positive for HCV antibody, and positive for quantitative detection of HCV ribonucleic  acid amplification). (21) Severe active infection, including but not limited to bacteremia, severe pneumonia,  etc., occurred within 2 weeks before the first dose; active infection that received therapeutic  intravenous antibiotics within 2 weeks before the first dose. (22) Patient with active autoimmune disease, such as rheumatism, rheumatoid, etc. (23) The investigator considers that the patient is not suitable for participating in this study  (e.g., study treatment is not in the best interest of patient, patients with mental disorder,  patients with poor compliance, etc.).                 |                                                                                                                                                          |
| Investigational | Generic name: BB102 tablets                                                                                                                              |
| Drug            | Dosage form: Tablet Active ingredient: BB102 Strength: 10 mg, 50 mg Storage condition: store in a sealed condition at room temperature Shelf life: 24 months tentatively Drug source: provided by the sponsor Dose levels: possibly 50 mg QD, 100 mg QD, 160 mg QD, 240 mg QD, 320 mg QD and  420 mg QD (for the dose escalation groups, the escalation doses may be adjusted according  to the previously obtained clinical trial data of BB102 tablets, e.g., adding dose groups of  520 mg QD and 600 mg QD) Administration route: Oral Administration method: ➢ For dose groups 1, 2, 3, 4, 5 and 6 in the dose escalation trial, subjects will be fasted  overnight for at least 10 hours before dosing on D1 and C1D21 and take BB102 tablets  with about 240 mL of water; no drinking is allowed from 1 h pre-dose to 1 h postdose; and no food is allowed within 2 h post-dose. Subjects will be on a normal diet.                                                                                                                                                          |  
➢ For dose groups 1, 2, 3, 4, 5 and 6 in the dose escalation trial, subjects will be fasted  
at least 2 hours before dosing on the other dosing days, and take BB102 tablets with water; no food is allowed within 1 h post-dose. Subjects will be on a normal diet.  
➢ For dose groups A in the dose escalation trial, subjects will be fasted overnight for at  
least 10 hours before dosing on D1 and C1D21, start eating a low-fat meal at 30 min before dosing on D1 and C1D21 (breakfast), finish the meal within 30 min and take  
BB102 tablets with about 240 mL of water at 30 min from the start of meal (if the  
meal takes more than 30 minutes, BB102 tablets should be administered immediately  
after the meal); no drinking is allowed from 1 h pre-dose to 1 h post-dose; no food is allowed within 4 h post-dose. Except for the low-fat meal (breakfast) on the specified days, subjects will be on a normal diet.  
Composition of the low-fat meal:  
Total calories (kcal) 400-500 Fat (g) 11-14 Calories from fat (%) 25  
An example of a low-fat breakfast* - Eight ounces milk (1 percent fat)  
- One boiled egg - One packet flavored instant oatmeal  
made with water  
*Note: 25% of calories are derived from fat. Substitutions can be made to this meal, if the content, volume, and viscosity are maintained. A registered dietician at the study  
site should determine the appropriate meal to be consumed, based on the fat and calorie requirements assigned to the patient for that treatment day. The start/stop time of meal consumption, and estimated % of test meal consumed (based on fat and  
caloric content), must be listed in the meal record electronic case report form (eCRF) for patients allocated in exploratory food effect group.  
➢ For dose group A in the dose escalation trial, subjects will take BB102 tablets with  
water within 30 minutes following the meal on the other dosing days; no food is  
allowed within 1 h post-dose. Subjects will be on a normal diet.  
➢ In the expansion trial, subjects will be fasted for at least 2 hours before dosing and  
take BB102 tablets with water; no food is allowed within 1 h post-dose. Subjects will  
be on a normal diet. Note: The administration method of the expansion trial may be adjusted according to the previously obtained food effect evaluation results of BB102 tablets.  
Dosing frequency and cycles: once daily in 21-day cycles (the dosing frequency and cycle setting may be adjusted according to the previously obtained clinical trial data of BB102  
tablets). In the dose escalation trial, dose interruption, resumption and permanent discontinuation **during the DLT observation period:**  
➢ No dose adjustment is allowed in the DLT observation period, but the doses may be  
interrupted, resumed and permanently discontinued.  
➢ If several toxicities occur at the same time, dose interruption, resumption and  
permanent discontinuation should be carried out according to the most serious  
toxicity.  
(1) During the DLT observation period, if the subject develops DLT, the doses should be  
interrupted, and supportive treatment should be given as needed. The doses can be continued when the dosage has been administered before dose interruption is more than 75% of the scheduled dose, and the subject recovers to grade ≤1 or baseline (or, recovers  
to grade ≤2 and the investigator believes that there is no safety risk).  
(2) If the subject develops DLT again, the doses should be permanently discontinued,  
and unscheduled safety follow-up should be arranged until the toxicity is resolved or  
stabilized.  
(3) If the subject has other non-DLT toxicities, dose interruption needs to be determined  
according to the investigator's medical assessment, and supportive treatment will be provided as needed.  
Dose interruption, resumption, adjustment and permanent discontinuation in postDLT observation period of dose escalation trial and during the dosing period in the  
expansion trial:  
➢ If the AE is attributable to BB102 tablets according to the investigator's judgment,  
dose interruption, resumption, adjustment and permanent discontinuation will be  
performed according to the following table. If there is any other situation not  
described in the table below, the sponsor and investigator will decide whether to  
interrupt, resume, adjust, or permanently discontinue the dose after a comprehensive  
assessment of the benefits and risks.  
➢ Subjects can be given appropriate supportive treatment to relieve symptoms and signs  
of toxic reactions.  
➢ Dose interruption, resumption, adjustment and permanent discontinuation should be  
perfomed according to the most serious toxic reaction when several toxic reactions  
occur simultaneously.  
➢ Once the dose is decreased, up-titration to the previous level is not allowed.  
➢ A maximum of 2 dose interruptions is allowed for each subject, and each interruption  
shall not exceed 14 days. If a 3rd dose interruption is required, or a dose interruption  
is required for >14 days, permanent discontinuation is required for the subject unless  
it is considered that the continuation of BB102 tablets treatment at an appropriate dose  
is in the best interest of the patient after the sponsor and the investigator comprehensively evaluate the benefits and risks.  
➢ Rules for dose interruption, resumption, adjustment and permanent discontinuation  
are shown in the table below.  
| expansion trial: ➢ If the AE is attributable to BB102 tablets according to the investigator's judgment,  dose interruption, resumption, adjustment and permanent discontinuation will be performed according to the following table. If there is any other situation not  described in the table below, the sponsor and investigator will decide whether to  interrupt, resume, adjust, or permanently discontinue the dose after a comprehensive  assessment of the benefits and risks. ➢ Subjects can be given appropriate supportive treatment to relieve symptoms and signs  of toxic reactions. ➢ Dose interruption, resumption, adjustment and permanent discontinuation should be  perfomed according to the most serious toxic reaction when several toxic reactions  occur simultaneously. ➢ Once the dose is decreased, up-titration to the previous level is not allowed. ➢ A maximum of 2 dose interruptions is allowed for each subject, and each interruption  shall not exceed 14 days. If a 3rd dose interruption is required, or a dose interruption  is required for >14 days, permanent discontinuation is required for the subject unless  it is considered that the continuation of BB102 tablets treatment at an appropriate dose  is in the best interest of the patient after the sponsor and the investigator  comprehensively evaluate the benefits and risks. ➢ Rules for dose interruption, resumption, adjustment and permanent discontinuation are shown in the table below. Hematologic toxicity a Rules for dose interruption, resumption, adjustment and permanent discontinuation b Neutrophil count decreased Grade 1-2 Continue the study treatment at the original dose level. Administration interruption until the toxicity is  resolved to grade ≤2. ➢ Resume the study treatment at the original dose  level if the toxicity is resolved within ≤7 days.Grade 3   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| ➢                                                                                                                                                                                                            | Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within 7- 14 days.                                                                                                                                                                                                                                                         |                       |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|
| ➢                                                                                                                                                                                                            | Discontinue permanently                                                                                                                                                                                                                                                                                                                                                 | if the toxicity is    |
| resolved within >14 days.                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                         |                       |
| Administration interruption                                                                                                                                                                                  | until the toxicity is                                                                                                                                                                                                                                                                                                                                                   |                       |
| resolved to grade ≤2. ➢ Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within ≤7 days. ➢ Discontinue permanently if the toxicity is  resolved within >7 days.  |                                                                                                                                                                                                                                                                                                                                                                         |                       |
| Febrile neutropenia Grade 4                                                                                                                                                                                  | Administration interruption                                                                                                                                                                                                                                                                                                                                             | until the toxicity is |
| resolved. ➢ Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within  ≤14 days. ➢ Discontinue permanently if the toxicity is  resolved within >14 days.           |                                                                                                                                                                                                                                                                                                                                                                         |                       |
| Grade 4                                                                                                                                                                                                      | Discontinue permanently.                                                                                                                                                                                                                                                                                                                                                |                       |
| Platelet count decreased Grade 1-2                                                                                                                                                                           | Continue the study treatment at the original dose level.                                                                                                                                                                                                                                                                                                                |                       |
| Grade 3                                                                                                                                                                                                      | Administration interruption until the toxicity is  resolved to grade ≤1. ➢ Resume the study treatment at the original dose  level if the toxicity is resolved within ≤7 days. ➢ Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within 7- 14 days. ➢ Discontinue permanently if the toxicity is  resolved within >14 days. |                       |
| Grade 3                                                                                                                                                                                                      | Administration interruption                                                                                                                                                                                                                                                                                                                                             | until the toxicity is |
| resolved to grade ≤1. ➢ Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within ≤7  days. ➢ Discontinue permanently if the toxicity is  resolved within >7 days. |                                                                                                                                                                                                                                                                                                                                                                         |                       |
| Anemia Grade 1-2                                                                                                                                                                                             | Continue the study treatment at the original dose level.                                                                                                                                                                                                                                                                                                                |                       |
| Grade 4 Grade 3                                                                                                                                                                                              | Administration interruption until the toxicity is  resolved to grade ≤2.                                                                                                                                                                                                                                                                                                |                       |  
| ➢                                                                                                                                                                                                            | Resume the study treatment at the original dose  level if the toxicity is resolved within ≤7 days.                                                                                                                                                                                                                                                     |                    |           |               |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|-----------|---------------|
| ➢                                                                                                                                                                                                            | Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within 7- 14 days.                                                                                                                                                                                                                                        |                    |           |               |
| ➢                                                                                                                                                                                                            | Discontinue permanently                                                                                                                                                                                                                                                                                                                                | if the toxicity is |           |               |
| resolved within >14 days.                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                        |                    |           |               |
| Administration interruption                                                                                                                                                                                  | until the toxicity is                                                                                                                                                                                                                                                                                                                                  |                    |           |               |
| resolved to grade ≤2. ➢ Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within ≤7  days. ➢ Discontinue permanently if the toxicity is  resolved within >7 days. |                                                                                                                                                                                                                                                                                                                                                        |                    |           |               |
| Other hematologic toxicity Grade 1-2                                                                                                                                                                         | Continue the study treatment at the original dose level.                                                                                                                                                                                                                                                                                               |                    |           |               |
| Grade 4                                                                                                                                                                                                      | Administration interruption until the toxicity is  resolved to grade ≤2. Resume the study treatment at the original dose level  after the toxicity is resolved to grade ≤2.                                                                                                                                                                            |                    |           |               |
| Grade 3                                                                                                                                                                                                      | Administration interruption until the toxicity is  resolved to grade ≤2. Resume the study treatment at the original dose level  after the toxicity is resolved to grade ≤2 (the sponsor  and investigator will decide whether to continue the  administration after a comprehensive assessment of  the benefits and risks).                            |                    |           |               |
| Abnormal grade 4 laboratory  test results that are not lifethreatening judged by the  investigator                                                                                                                                                                                                              | Administration interruption until the toxicity is  resolved to grade ≤2. Continue the study treatment at the dose reduced by  one level c after the toxicity is resolved to grade ≤2.                                                                                                                                                                  |                    |           |               |
| Grade 4                                                                                                                                                                                                      | Rules                                                                                                                                                                                                                                                                                                                                                  | for                | dose      | interruption, |
| Nonhematologic toxicity a                                                                                                                                                                                    | resumptionadjustment                                                                                                                                                                                                                                                                                                                                   | and                | permanent |               |
| discontinuation b                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                        |                    |           |               |
| Creatinine increased Grade 1                                                                                                                                                                                 | Continue the study treatment at the original dose level. Administration interruption until the toxicity is  resolved to baseline. ➢ Resume the study treatment at the original dose  level if the toxicity is resolved within ≤7 days. ➢ Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within >7  days. |                    |           |               |
| Grade 2                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                        |                    |           |               |  
| Grade 3-4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Discontinue permanently.                                                                                                                                                                                                                                                                                                                                                                                                       |                       |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|
| Blood bilirubin increased Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Continue the study treatment at the original dose level. Administration interruption until the toxicity is  resolved to baseline. ➢ Resume the study treatment at the original dose  level if the toxicity is resolved within ≤7 days. ➢ Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within >7  days. ➢ Discontinue permanently if the toxicity is  resolved within >14 days. |                       |
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Administration interruption                                                                                                                                                                                                                                                                                                                                                                                                    | until the toxicity is |
| resolved to baseline. ➢ Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within ≤7  days. ➢ Discontinue permanently if the toxicity is  resolved within >7 days. Note: Continue the  study treatment at the dose reduced by one level c at the discretion of the investigator if the grade  3 increase in blood bilirubin is only due to the  increase in indirect bilirubin (unconjugated  bilirubin), and hemolytic factors (e.g., peripheral  blood smear examination and haptoglobin assay)  have been excluded according to the guidelines  of each study center. |                                                                                                                                                                                                                                                                                                                                                                                                                                |                       |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Discontinue permanently. Note: Continue the study treatment at the dose reduced  by one level c at the discretion of the investigator if the  grade 4 increase in blood bilirubin is only due to the  increase in indirect bilirubin (unconjugated bilirubin),  and hemolytic factors (e.g., peripheral blood smear  examination and haptoglobin assay) have been  excluded according to the guidelines of each study  center. |                       |
| AST or ALT increased Grade 1-2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Continue the study treatment at the original dose level.                                                                                                                                                                                                                                                                                                                                                                       |                       |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Administration interruption                                                                                                                                                                                                                                                                                                                                                                                                    | until the toxicity is |
| resolved to grade ≤2 (liver cancer or liver metastases) or grade ≤1. ➢ Resume the study treatment at the original dose  level if the toxicity is resolved within ≤7 days.                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                |                       |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                |                       |  
| ➢                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Continue the study treatment at the dose reduced  by one level c if the toxicity is resolved within 7- 14 days.   |                       |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|-----------------------|
| ➢                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Discontinue permanently                                                                                           | if the toxicity is    |
| resolved within >14 days.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                   |                       |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Discontinue permanently.                                                                                          |                       |
| Other                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | nonhematologic                                                                                                    |                       |
| toxicity Grade 1-2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Continue the study treatment at the original dose level.                                                          |                       |
| Grade 3 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 and ALP increased.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Administration interruption                                                                                       | until the toxicity is |
| resolved to grade ≤2. Resume the study treatment at the original dose level  after the toxicity is resolved to grade ≤2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                   |                       |
| Grade 3 Note: Toxicities with no safety  risk at the discretion of the  investigator are excepted, such  as grade 3 nausea, vomiting,  diarrhea, asthenia, constipation, loss of appetite,  mucositis, GGT increased and  ALP increased.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Administration interruption                                                                                       | until the toxicity is |
| resolved to grade ≤2 or grade ≤1. Resume the study treatment at the dose reduced by one  level c after the toxicity is resolved to grade 2 (only  when the investigator believes resuming the study  treatment poses no safety risk to the subject) or grade ≤1.  Administration interruption until the toxicity is  resolved to grade ≤2 or grade ≤1. Resume the study treatment at the dose reduced by one  level c after the toxicity is resolved to grade 2 (only  when the investigator believes resuming the study  treatment poses no safety risk to the subject) or grade  ≤1 (the sponsor and investigator will decide whether  to continue the administration after a comprehensive  assessment of the benefits and risks). |                                                                                                                   |                       |
| Grade 4 Toxicities with no safety risk at  the discretion of the  investigator are excepted, such  as grade 4 GGT increased and  ALP increased. Abnormal grade 4 laboratory  test results that are not lifethreatening judged by the  investigator (such as grade 4  GGT increased and ALP  increased).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Discontinue permanently.                                                                                          |                       |
| Abbreviations: ALP = alkaline phosphatase; DLT = dose-limiting toxicity; GGT = γglutamyltransferase.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                   |                       |  
| Note: a. Applicable to all hematologic toxicities (if a hematologic toxicity is related to  other non-hematologic clinical events, refer to the rules for dose interruption, resumption  and adjustment of non-hematologic toxicities). B: The rules may be modified based on the previously obtained clinical trial data of BB102  tablets. C: Available dose levels of BB102 tablets include 50 mg QD, 100 mg QD, 160 mg QD,  240 mg QD, 320 mg QD and 420 mg QD. If dose reduction is required at the starting dose  level, the subject should discontinue the treatment permanently. Criteria for study treatment discontinuation (whichever occurs first): - Subject has disease progression, unless the investigator believes the subject can still  benefit from the study treatment clinically. - The investigator determines that the subject cannot clinically benefit from the study  treatment and continued study treatment may pose an unacceptable risk to the subject. - There is major protocol deviation. After enrollment, the subject is found to be noncompliant with enrollment criteria in the study protocol or does not follow  requirements in the study protocol, and the investigator believes that continued study  treatment may pose an unacceptable risk to the subject. - The subject has a poor compliance, uses prohibited concomitant medications without  permission or fails to attend visits on schedule, which affects the evaluation of  efficacy and/or safety, and the subject is considered inappropriate to continue the  study at the discretion of the investigator.  - The subject experiences a particular comorbidity or complication, which, in the  discretion of the investigator, makes it inappropriate to continue the study treatment. - The subject experiences an intolerable toxicity. - Subject pregnancy. - Subject is lost to follow-up for more than 8 weeks. - Subject death. - Any other conditions in which the investigator believes that the study should be  terminated. - The subject refuses to continue the study treatment. - The study site is closed prematurely, the study is prematurely terminated or the study  ends. Notes: After study treatment discontinuation, subjects will enter into the follow-up  period (unless follow-up is not applicable).             |                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
|-------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Comparators | None.                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Concomitant | Concomitant medications include any medications other than the study drug (including                                                                                                                                                                                                                                                                                                                                                                    |
| Medications | prescription drugs, over-the-counter drugs, natural extracts, nutritional supplements and  traditional Chinese medicines) used by subjects from the start of first dose to 28 days after  the last dose of study treatment. Note: Medications used by subjects at screening will be  recorded as medication history. (1) For the dose escalation trial and expansion trial, the following drugs/therapies  will be allowed during the treatment period: |  
➢ Bisphosphonates for treating bone metastasis. Note: Bisphosphonate therapy should  
be administered according to the local medical practice.  
➢ Palliative radiotherapy for relieving pain caused by bone lesion, on the condition that  
this lesion has existed at the time of enrollment and the investigator clarifies the requirement of palliative radiotherapy does not represent disease progression. Note: As there is currently a lack of data on the interaction between BB102 tablets and  
radiotherapy, BB102 tablets therapy should be interrupted at 1 day before palliative radiotherapy and throughout the radiotherapy period and be resumed after the acute radiotoxicity recovers to baseline level. Note: Palliative radiotherapy is not allowed  
during the DLT observation period; if the study drug dose received by a subject during the DLT observation period is less than 75% of the scheduled dose due to use of palli'tive therapy and no DLT occurs, the corresponding dose group needs one more  
subject for replacement.  
➢ Therapeutic drugs used for AE (dose escalation trial), such as choleretics, but only the  
non-prohibited medications can be used.  
➢ Preventive drugs and therapeutic drugs used for AE (expansion trial), such as  
choleretics, but only the non-prohibited medications can be used.  
(2) In the dose escalation trial and expansion trial, the following drugs/therapies will  
be prohibited during the treatment period:  
➢ Anti-tumor therapies rather than the study drug (including but not limited to  
chemotherapy, radiotherapy, immunotherapy, anti-tumor biotherapy, etc.), including  
state-approved Chinese traditional patent drugs with an anti-tumor effect.  
➢ Adjuvants (e.g., preventive leukocyte increasing drugs, antiemetics, etc.) related to  
anti-tumor therapy (for dose escalation trial only).  
➢ Strong CYP3A4 inhibitors, strong CYP3A4 inducers, strong CYP3A5 inhibitors,  
strong CYP3A5 inducers, sensitive CYP3A4 substrates with a narrow therapeutic  
index, and sensitive CYP2B6 substrates with a narrow therapeutic index (Appendix IV).  
(3) In the dose escalation trial and expansion **trial, the following drugs/therapies can**  
be used with cautious **during the treatment period:**  
➢ Moderate or weak CYP3A4/5 inhibitors and inducers. ➢ Breast cancer resistance protein (BCRP) substrates, P-glycoprotein (P-gp) substrates,  
OAT1 substrates, OAT3 substrates, OATP1B3 substrates, MATE1 substrates, and  
MATE2-K substrates with a narrow therapeutic index (Appendix V).  
➢ Strong BCRP inhibitors and strong P-gp inhibitors (Appendix V). ➢ Drugs which are known to or may prolong QT interval or induce tip torsion ventricular  
tachycardia (Appendix VI).  
➢ Given that FGFR4 inhibitor can increase CYP7A1 expression, try not to use drugs  
that can increase CYP7A1 expression or enzyme activity (e.g., atorvastatin, troglitazone); try not to use cholesterol (CYP7A1 substrates)-containing drugs.  
(4) **Prevention and management of expected adverse drug reactions (ADRs):**  
The actual ADR treatment measures will be taken by the investigator according to the actual situation of the subjects in combination with clinical practice and relevant  
| guidelines. The following suggestions are only for reference. For common ADRs in the  dose escalation trial, prophylaxis can be given in advance during the expansion trial. ➢ Diarrhea: Among the adverse effects of FGFR inhibitor, diarrhea's incidence is 15%- 60%, which may be related to preventing the binding of FGF19 and FGFR4. The  homeostasis of bile acids will be regulated after FGF19 binding with FGFR4, while  bile acids have effects on colonic mucosal permeability. It is recommended to continue the study treatment at the original dose level, and loperamide, probiotics, and  smecta (montmorillonite powder) should be given to treat ADR at the same time when  drug-related grade 1-2 diarrhea occurs during the clinical trial. If grade 3 diarrhea  occurs, it is recommended to interrupt the study treatment, and loperamide, probiotics,  and smecta (montmorillonite powder) should be given to treat ADR at the same time  (codeine and prophylactic antibiotics may be used if necessary), the addition of  somatostatin may be considered in severe conditions. If grade 4 diarrhea occurs, it is  recommended to discontinue the study treatment permanently, at the same time, the above symptomatic treatment should be given. ➢ Asthenia: FGFR4 has the function of regulating the differentiation of muscle cells and  tissue repair. If asthenia occurs in the trial, it is considered to be related to the  inhibition of the physiological function of FGFR4. It is recommended to continue the  study treatment at the original dose level, and have more rest at the same time when  drug-related grade 1-2 asthenia occurs during the clinical trial. If grade 3 asthenia  occurs, it is recommended to discontinue the study treatment permanently and have  more rest at the same time. ➢ Nausea/vomiting: They are not caused by FGFR4 physiological mechanism and can  be considered as the gastrointestinal irritation of the investigational drug. It is  recommended to continue the study treatment at the original dose level, and  metoclopramide and so on should be given to treat ADR at the same time when drugrelated grade 1-2 nausea/vomiting occurs during the clinical trial. If grade 3  nausea/vomiting occurs, it is recommended to interrupt the study treatment, and  metoclopramide and so on should be given to treat ADR at the same time. If grade 4 nausea/vomiting occurs, it is recommended to discontinue the study treatment  permanently, and the above symptomatic treatment should be given at the same time. ➢ Fever: Generally, it may be the non-inflammatory fever caused by the death or rupture  of cancer cells. It is recommended to continue the study treatment at the original dose  level, at the same time, strengthen body temperature monitoring, and perform physical  cooling, ice compress and drink warm water if necessary when drug-related grade 1  fever occurs during the clinical trial. If grade 2 fever occurs, it is recommended to continue the study treatment at the original dose level, and cooling medications (e.g.,  dexamethasone, loratadine, etc.) should be given to treat ADR at the same time. If  grade 3 fever occurs, it is recommended to interrupt the study treatment and the above  symptomatic treatment should be given at the same time. If grade 4 fever occurs, it is  recommended to discontinue the study treatment permanently, and the above  symptomatic treatment should be given at the same time. ➢ Hepatotoxicity: It is considered to be caused by damage to liver cells or functional  overload. It is recommended to continue the study treatment at the original dose level,  and hepatoprotective medications [e.g., Chinese traditional patent drug, polyene   |
|---|  
| phosphatidylcholine, reduced glutathione, magnesium isoglycyrrhizinate, simetai  (adenosylmethionine butanedisulfonate enteric-coated tablet)] should be given for  symptomatic treatment at the same time when drug-related grade 1-2 hepatotoxicity occurs during the clinical trial. If grade 3 hepatotoxicity occurs, it is recommended to  interrupt the study treatment and the above symptomatic treatment should be given at  the same time. If grade 4 hepatotoxicity occurs, it is recommended to discontinue the  study treatment permanently, and the above symptomatic treatment should be given  at the same time.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Any prescription drugs, over-the-counter drugs, natural extracts, nutritional supplements,  traditional Chinese medicines, herbal medicines and vitamins should be reviewed and  approved by the investigator. All information on concomitant medications should be  recorded in the subjects' medical records and reported on the electronic eCRF. For the  specifications on concomitant medications, see Section 6.2 of the main text.                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Throughout the Phase I study, all subjects need to receive study treatment, safety                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Procedures                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | assessment, PK blood sampling and efficacy evaluation according to the visit schedule.  See Study Flow Chart for details. The tumor tissue specimens will be collected and preserved. For the specific collection,  handling and storage methods, refer to the related standard operation procedure (SOP) of  each study site. Computed tomography (CT) and other electronic documents should be  saved on disc. The cut-off time for data collection of this Phase I study is 8 weeks after the last subject  starts the study treatment, unless the entire study is prematurely terminated. At the time of  study data collection cutoff, if a subject can tolerate the study drug and remains complete  response (CR)/partial response (PR)/stable disease (SD) and is willing to continue the study  drug treatment, the investigator believes that the subject will still clinically benefit from  the continued treatment and the investigator confirms that there is no problem in drug  supply after discussion with the sponsor, the subject can continue the study drug treatment  (i.e., compassionate use), until he/she meets the criteria for study treatment discontinuation  or there is a drug supply problem (whichever occurs first). During the compassionate use,  drug-related AEs and serious adverse events (SAEs) will be recorded according to the  relevant national regulations, and the SAEs will be reported to the sponsor/CRO safety  department. Routine safety monitoring should be continued as needed. The investigator  will select and schedule test items at his/her own discretion and should preserve relevant  documents in the source files. The sponsor will not routinely collect relative results of these  tests. Data collected during compassionate use will not be included in statistical analysis  of the study. |
| Study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Dose escalation trial                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| Endpoints                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Primary endpoints: - Safety and tolerability of BB102 tablets (fasted or fed): Incidences of AEs and  SAEs; abnormalities or changes in laboratory tests, vital signs, ECG, physical  examination and ECOG score. - DLT of BB102 tablets (fasted or fed): Classification, severity and frequency of  DLT. Secondary endpoints:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |  
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | PK parameters of BB102 tablets (fasted): Maximum plasma concentration (Cmax),  time to maximum plasma concentration (Tmax), lag time (tlag), elimination rate  constant (Kel), T1/2, area under the concentration-time curve from 0 to the time point  of last quantifiable concentration (AUC0-t), area under the concentration-time curve  from time 0 to infinity (AUC0-inf), apparent clearance (CLz/F), apparent volume of  distribution (Vz/F), mean residence time (MRT), steady-state minimum plasma  concentration (Css, min), steady-state maximum plasma concentration (Css, max), average  steady-state plasma concentration (Css, av), area under the concentration-time curve  during a dosing interval at steady state (AUCss), steady-state degree of fluctuation  (DF) and accumulation ratio (Rac) of BB102 (and its main metabolites, if applicable).   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | PK parameters of BB102 tablets (fed): Cmax, Tmax, tlag, Kel, T1/2, AUC0-t, AUC0-inf,  CLz/F, Vz/F, MRT, Css, min, Css, max, Css, av, AUCss, DF and Rac of BB102 (and its main  metabolites, if applicable); whether food has an effect on the exposure parameters  (AUC0-inf, AUC0-t and Cmax) and the extent of effect.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Efficacy of BB102 tablets (fasted or fed): objective response rate (ORR), disease  control rate (DCR), duration of response (DOR), progression-free survival (PFS) and  overall survival (OS).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Relationship between biomarker and efficacy. Biomarkers include but are not  limited to protein expression level, amplification, mRNA level and activating  mutation profiles of FGF19 or FGFR4 in tumor tissues; bile acid precursors (e.g., 7- α-hydroxy-4-cholestene-3-one), total bile acids, total cholesterol, triglycerides (TG)  and serum FGF19 protein level in blood.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Correlation between plasma concentration of study drug and QTcF (C-QTcF  analysis).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Metabolites of BB102.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Expansion trial Primary endpoints: - Efficacy of BB102 tablets (fasted): ORR, DCR, DOR, PFS and OS. Secondary endpoints: - PK parameters of BB102 tablets (fasted): T1/2, AUC0-t, AUC0-inf, Css, min, Css, max,  Css, av, AUCss and DF of BB102 (and its main metabolites, if applicable). - Safety of BB102 tablets (fasted): Incidences of all AEs and SAEs; abnormalities or  changes in laboratory tests, vital signs, ECG, physical examination and ECOG score. - Relationship between biomarker and efficacy. Biomarkers include but are not  limited to protein expression level, amplification, mRNA level and activating  mutation profiles of FGF19 or FGFR4 in tumor tissues; bile acid precursors (e.g., 7- α-hydroxy-4-cholestene-3-one), total bile acids, total cholesterol, TG and serum  FGF19 protein level in blood. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| Statistical                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Statistical analysis sets:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Analysis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | ① Screening set: All subjects who signed the ICF. The screening set is used to analyze  the number of subjects screened, number of subjects enrolled and number of screening  failures.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |  
② **Safety set (SS):** All subjects who are enrolled and have taken the study drug. SS is used for the description of demographic data, description of baseline characteristics, safety analysis and efficacy analysis.  
③ **DLT analysis set (DS):** All subjects who are enrolled and have taken the study drug, but excluding subjects who receive study drug at a dose less than 75% of the scheduled dose for reasons other than toxicities attributable to study drug during the DLT observation period. DS is used for the analysis and summary of DLT.  
④ PK **analysis set (PKS):** All subjects who are enrolled, have taken the study drug, have at least one PK data for statistical analysis and have no any protocol deviation (e.g., missed dosing of BB102 tablets) that significantly affects the PK parameters [e.g., area under the concentration-time curve (AUC), Cmax, etc.] during the treatment cycle or dosing period containing blood sampling time point. Whether a subject is included into PKS will be determined case by case on the data review meeting. PKS is used for the analysis of PK
parameters.  
⑤ **Biomarker analysis set (BS):** All subjects who have at least one biological sample for biomarker analysis in the SS. BS is used for the analysis of relationship between biomarker and efficacy.
clinical trial protocol
general principles for statistics

SAS® 9.4 or updated version (SAS Institute, Inc., Cary, North Carolina) will be used for statistical analysis.  
Quantitative data will be described with the number of subjects of non-missing, mean, standard deviation, median, lower quartile, upper quartile, maximum and minimum. Qualitative data will be statistically described using the number, frequency and percentage of non-missing subjects. If necessary, the two-sided 95% confidence interval (95% CI) for the percentage will be calculated. Baseline of safety endpoints is the most recent data prior to the first dose (data at screening are acceptable), including laboratory tests, vital signs, ECG, physical examination and ECOG score. Prior medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) (current or updated version). Previous medications and concurrent/concomitant medications will be coded according to the World Health Organization (WHO) Drug Dictionary (current or updated version). Since this study is a Phase I trial, only descriptive statistics will be provided, and no hypothesis test will be performed. Safety, PK and efficacy analyses will be performed for the dose escalation trial and expansion trial separately. In the dose escalation trial, it will be summarized overall and by dose group. In addition, it should also be summarized by gender.  
The statistical analysis methods will be described in detail in the Statistical Analysis Plan.  
Statistical method:
(1) **Subject disposition analysis**
Information of screening failures will be tabulated and summarized. Subjects included in each analysis set will be summarized.  
For the enrolled subjects, the number of subjects with treatment discontinuation, number of subjects who terminate the study and percentage of reasons will be summarized.
clinical trial protocol
(2) analysis of demographics and

The demographic data and baseline characteristics will be descriptively summarized, including gender, age, race, ethnicity, body height, body weight, body mass index (BMI),
prior medical history, medication history, history of all neoplastic diseases, history of all anti-tumor therapies, family history, surgical history, allergic history, smoking history and history of drug abuse/dependence.
clinical trial protocol
(3) analysis of compliance and

Descriptive statistical analysis will be performed for the planned dose and actual dose by the following formula:
Compliance (%) = actual dose/planned dose × 100%.  
The frequency and percentage of concomitant medications occurring during the dosing period will be summarized. The concomitant medication of subjects will be tabulated in detail.
clinical trial protocol
(4) safety analysis

Drug safety will be evaluated by analyzing the incidences of AEs, ADRs, grade ≥3 AEs and SAEs, as well as abnormalities or changes in laboratory tests, vital signs, ECG,
physical examination and ECOG score.  
AEs, ADRs, grade ≥3 AEs and SAEs will be coded according to MedDRA (current or updated version), and their incidences will be summarized according to system organ class, preferred term and the severity (CTCAE, Grades 1-5), respectively. The number of subjects with different AEs will be summarized, regardless of the number of times each subject actually reported the event. Laboratory test parameters of subjects will be summarized before and after dosing.  
For vital signs, ECG and physical examination, subjects with abnormal changes during the study will be described. For ECOG score, patients' score and change in the score will be described.  
If applicable, the data listings before and after dosing will be provided, and the mean ±
standard deviation will be calculated. Patients with parameters being normal pre-dose but abnormal post-dose (regardless of the clinically significance) will be listed.  
(5) **DLT analysis**
Number of subjects with DLT as well as the category, severity and incidence of DLT will be summarized.
clinical trial protocol
(6) pk parameters analysis

Individual concentration-time curve of BB102 (and its main metabolites, if applicable) of each subject. Moreover, mean (Mean ± SD) concentration-time curve of BB102 (and its main metabolites, if applicable) will be plotted by dose group.  
The PK parameters of BB102 (and its main metabolites, if applicable) will be analyzed using the non-compartment analysis method of the Phoenix WinNonlin 8.3.1 or updated version (Pharsight Corp., Mountain View, CA, USA) software. For the plasma PK parameters of BB102 (and its main metabolites, if applicable),
descriptive statistical analysis will be performed by dose group, with the descriptive statistics including the number of samples, mean, standard deviation, coefficient of  
variation, minimum and maximum. If considered necessary by the investigator and the  
sponsor, the linear relationship between the AUC and Cmax of BB102 (and its main  
metabolites, if applicable) and dose can be analyzed.  
(7) **Analysis of food effect**  
Data analysis will be performed by the average bioequivalence method with fasted condition as the reference, and the exposure parameters (AUC0-inf, AUC0-t and Cmax) will  
be log transformed using natural logarithm to calculate the geometric mean ratio of fed group to fasted group and its 90%CI. If the 90%CI of the geometric mean ratios (fed  
group/fasted group) of AUC0-inf (or AUC0-t) and Cmax all fall within the range of 80%-  
125%, it can be preliminarily concluded that food has no significant effect on the  
bioavailability of the drug.  
(8) **Efficacy analyses**  
- **ORR:** The proportion of patients with a best overall response of CR and PR as  
assessed per RECIST v1.1 in all patients.  
- **DCR:** The proportion of patients with a best overall response of CR, PR and SD  
(duration of SD ≥12 weeks) as assessed per RECIST v1.1 in all patients.  
- **DOR:** The duration from the firstly documented CR or PR to the date of confirmed  
objective tumor progression (based on RECIST v1.1) or death for the subjects with a best overall response of CR or PR. For the patients who have no objective tumor  
progression or death at the end of trial, the date of the last objective tumor assessment  
will be taken as the censored date of DOR.  
- **PFS:** The duration from the first dose of study drug to objective tumor progression  
(based on RECIST v1.1) or death. For the patients who have no objective tumor  
progression or death at the end of trial, the date of the last objective tumor assessment will be taken as the censored date of PFS.  
- OS: The duration from the first dose of study drug to death. For patients who are alive  
at the end of trial, their last date known to be alive will be used as the censored date of OS.  
Point estimates of ORR and DCR and their two-sided 95%CI will be calculated. The twosided 95% CI of ORR and DCR are calculated based on the Clopper-Pearson method.  
Meanwhile, the number and percentage of subjects with CR, PR, SD and disease progression will be presented.  
For DOR (for subjects experiencing CR and/or PR only), PFS and OS, Kaplan-Meier  
method will be adopted to calculate the median, lower quartile, upper quartile and twosided 95% CI, and survival curves will be drawn.  
For ORR, the estimated objective is shown in the table below.  
Estimated objective:  
Population: FGF19 or FGFR4 positive advanced primary HCC or other  
advanced solid tumors  
Treatment: See Section 6 of the main body for details Endpoint: ORR  
Intercurrent events and handling strategies:  
- Discontinuation of study treatment or initiation of new  
anticancer therapy prior to CR or PR will be handled according to the while-on-treatment strategy.  
Summary at the  
population level:  
ORR and corresponding two-sided 95%CI (estimated by Clopper-Pearson method) will be calculated  
For DOR, the estimated objective is shown in the table below.  
Estimated objective:  
Population: FGF19 or FGFR4 positive advanced primary HCC or other  
advanced solid tumors  
Treatment: See Section 6 of the main body for details Endpoint: DOR  
Intercurrent events and  
handling strategies:  
- Discontinuation of study treatment or initiation of new  
anticancer therapy prior to objective tumor progression  
or death will be handled according to the hypothetical  
strategy.  
Summary at the  
population level:  
The variables of event time will be descriptively summarized, and KM curves will be plotted  
For other efficacy measures (DCR, PFS and OS), an estimation method like that of ORR  
or DOR will be used.  
(9) **Biomarker analysis**  
The relationship between biomarker and efficacy will be analyzed, and the correlation will be inferred preliminarily.  
(10) **C-QTcF analysis**  
If considered necessary by the investigator and the sponsor, C-QTcF modeling analysis will be performed based on the data features and appropriate models to explore C-QTcF  
and investigate the possibility of QTC interval prolongation induced by BB102.  
(11) **Analysis of metabolites**  
Metabolites of BB102 will be identified. The metabolites and subjects will be tabulated.  
(12) **Subgroup analysis**  
Subgroup analysis will be performed by gender.  
(13) **Interim analysis**  
Not applicable.  
| Study Flow Chart                         |                                                                |                                      |                  |    |    |               |    |    |
|------------------------------------------|----------------------------------------------------------------|--------------------------------------|------------------|----|----|---------------|----|----|
| Screen ing  period/ baselin e            | End of  treatme nt visit  (EOT)                                |                                      |                  |    |    |               |    |    |
| Period                                   | Single-dosing period*                                          | Multiple-dosing period               | Follow-up period |    |    |               |    |    |
| The  2 nd                                | From  the 2nd cycle                                            | Within  7 days  after the  last dose |                  |    |    |               |    |    |
| D-28                                     |                                                                |                                      |                  |    |    |               |    |    |
| Time (days)                              | D1                                                             | D2                                   | D3               | D4 | D5 | The 1st cycle |    |    |
| to D-1                                   | Safety  visit                                                  | Subsequent  follow-up                |                  |    |    |               |    |    |
| cycle                                    | Follow-up  once every 8  weeks (±7  days) after  the last dose |                                      |                  |    |    |               |    |    |
| 28 days  (±7 days)  after the  last dose |                                                                |                                      |                  |    |    |               |    |    |
| C1D8 (±1  day)                           | C2D1 (±1  day) CnD21 (±3  days)                                |                                      |                  |    |    |               |    |    |
| Per multiple-dosing                      | C1D1                                                           |                                      |                  |    |    |               |    |    |
| time (days)                              | C1D15 (±1 day)                                                 | C1D21 (±1 day)                       |                  |    |    |               |    |    |
| Informed consent 1                       | X                                                              |                                      |                  |    |    |               |    |    |
| Reviewing  inclusion/exclusion  criteria | X                                                              |                                      |                  |    |    |               |    |    |
| Demographics 2                           | X                                                              |                                      |                  |    |    |               |    |    |
| Medical history and                      | X                                                              |                                      |                  |    |    |               |    |    |
| medication history 3 Hematology 4        | X                                                              | X                                    | Xa               | Xa | Xa | Xb            | Xd | Xd |
| Urinalysis 5                             | X                                                              | X                                    | Xa               | Xa | Xa | Xc            | Xd | Xd |
| X (±1                                    |                                                                |                                      |                  |    |    |               |    |    |
| Stool routine 6                          | X                                                              | Xa                                   | Xa               | Xa | Xc | Xd            | Xd |    |
| day)                                     |                                                                |                                      |                  |    |    |               |    |    |  
| Screen ing  period/ baselin e            | End of  treatme nt visit  (EOT)                                |                                      |                  |    |    |               |    |    |    |    |
|------------------------------------------|----------------------------------------------------------------|--------------------------------------|------------------|----|----|---------------|----|----|----|----|
| Period                                   | Single-dosing period*                                          | Multiple-dosing period               | Follow-up period |    |    |               |    |    |    |    |
| The  2 nd                                | From  the 2nd cycle                                            | Within  7 days  after the  last dose |                  |    |    |               |    |    |    |    |
| D-28                                     |                                                                |                                      |                  |    |    |               |    |    |    |    |
| Time (days)                              | D1                                                             | D2                                   | D3               | D4 | D5 | The 1st cycle |    |    |    |    |
| to D-1                                   | Safety  visit                                                  | Subsequent  follow-up                |                  |    |    |               |    |    |    |    |
| cycle                                    | Follow-up  once every 8  weeks (±7  days) after  the last dose |                                      |                  |    |    |               |    |    |    |    |
| 28 days  (±7 days)  after the  last dose |                                                                |                                      |                  |    |    |               |    |    |    |    |
| C1D8 (±1  day)                           | C2D1 (±1  day) CnD21 (±3  days)                                |                                      |                  |    |    |               |    |    |    |    |
| Per multiple-dosing                      | C1D1                                                           |                                      |                  |    |    |               |    |    |    |    |
| time (days)                              | C1D15 (±1 day)                                                 | C1D21 (±1 day)                       |                  |    |    |               |    |    |    |    |
| Blood biochemistry 7                     | X                                                              | X                                    | Xa               | Xa | Xa | Xb            | Xd | Xd |    |    |
| Coagulation 8                            | X                                                              | X                                    | Xa               | Xa | Xa | Xb            | Xd | Xd |    |    |
| Vital signs 9                            | X                                                              | X                                    | X                | X  | X  | X             | X  | X  | Xb | X  |
| 12-lead ECG 10                           | X                                                              | X                                    | X                | X  | X  | X             | X  | X  | Xb | X  |
| Physical  examination 11                 | X                                                              | X                                    | X                | X  | X  | Xb            | X  |    |    |    |
| ECOG assessment                          | X                                                              | X                                    | X                | Xc | X  |               |    |    |    |    |
| Pregnancy-related  test 12               | X                                                              | X                                    | Xc               | X  |    |               |    |    |    |    |
| Echocardiography 13                      | X                                                              | X                                    | X                | X  |    |               |    |    |    |    |
| Serum etiological  test 14               | X                                                              |                                      |                  |    |    |               |    |    |    |    |  
| Screen ing  period/ baselin e                                                                   | End of  treatme nt visit  (EOT)                                |                                      |                  |    |    |               |    |    |    |
|-------------------------------------------------------------------------------------------------|----------------------------------------------------------------|--------------------------------------|------------------|----|----|---------------|----|----|----|
| Period                                                                                          | Single-dosing period*                                          | Multiple-dosing period               | Follow-up period |    |    |               |    |    |    |
| The  2 nd                                                                                       | From  the 2nd cycle                                            | Within  7 days  after the  last dose |                  |    |    |               |    |    |    |
| D-28                                                                                            |                                                                |                                      |                  |    |    |               |    |    |    |
| Time (days)                                                                                     | D1                                                             | D2                                   | D3               | D4 | D5 | The 1st cycle |    |    |    |
| to D-1                                                                                          | Safety  visit                                                  | Subsequent  follow-up                |                  |    |    |               |    |    |    |
| cycle                                                                                           | Follow-up  once every 8  weeks (±7  days) after  the last dose |                                      |                  |    |    |               |    |    |    |
| 28 days  (±7 days)  after the  last dose                                                        |                                                                |                                      |                  |    |    |               |    |    |    |
| C1D8 (±1  day)                                                                                  | C2D1 (±1  day) CnD21 (±3  days)                                |                                      |                  |    |    |               |    |    |    |
| Per multiple-dosing                                                                             | C1D1                                                           |                                      |                  |    |    |               |    |    |    |
| time (days)                                                                                     | C1D15 (±1 day)                                                 | C1D21 (±1 day)                       |                  |    |    |               |    |    |    |
| Administration of BB102 tablets is tentatively  scheduled as: oral, once daily in 21-day cycles |                                                                |                                      |                  |    |    |               |    |    |    |
| Study drug                                                                                      | X                                                              |                                      |                  |    |    |               |    |    |    |
| administration Dispensing/collectin g diary cards and  drugs                                    | X                                                              | X                                    | X                | X  |    |               |    |    |    |
| Tumor assessment 15                                                                             | X                                                              | X                                    | X                | X  | X  |               |    |    |    |
| Detection of  biomarkers 16                                                                     | X                                                              | X                                    | X                | X  | X  |               |    |    |    |
| X                                                                                               | X                                                              | X                                    | X                | X  | X  | X             | X  | X  | X  |
| PK blood sampling  17 Blood sampling for  identification of  metabolites 18                     | X                                                              | X                                    | X                | X  | X  |               |    |    |    |  
| Screen ing  period/ baselin e                                                         | End of  treatme nt visit  (EOT)                                                                                           |                                                                                                                           |                  |    |    |               |
|---------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------|------------------|----|----|---------------|
| Period                                                                                | Single-dosing period*                                                                                                     | Multiple-dosing period                                                                                                    | Follow-up period |    |    |               |
| The  2 nd                                                                             | From  the 2nd cycle                                                                                                       | Within  7 days  after the  last dose                                                                                      |                  |    |    |               |
| D-28                                                                                  |                                                                                                                           |                                                                                                                           |                  |    |    |               |
| Time (days)                                                                           | D1                                                                                                                        | D2                                                                                                                        | D3               | D4 | D5 | The 1st cycle |
| to D-1                                                                                | Safety  visit                                                                                                             | Subsequent  follow-up                                                                                                     |                  |    |    |               |
| cycle                                                                                 | Follow-up  once every 8  weeks (±7  days) after  the last dose                                                            |                                                                                                                           |                  |    |    |               |
| 28 days  (±7 days)  after the  last dose                                              |                                                                                                                           |                                                                                                                           |                  |    |    |               |
| C1D8 (±1  day)                                                                        | C2D1 (±1  day) CnD21 (±3  days)                                                                                           |                                                                                                                           |                  |    |    |               |
| Per multiple-dosing                                                                   | C1D1                                                                                                                      |                                                                                                                           |                  |    |    |               |
| time (days)                                                                           | C1D15 (±1 day)                                                                                                            | C1D21 (±1 day)                                                                                                            |                  |    |    |               |
| Anti-tumor  treatment and  survival information  after the end of  study treatment 19 | X                                                                                                                         | X                                                                                                                         |                  |    |    |               |
| Adverse event 20                                                                      | X                                                                                                                         | X-----------------------------------------------------------------------------------------------------------------------X |                  |    |    |               |
| DLT evaluation *                                                                      | X------------------------------------------------------------------X                                                      |                                                                                                                           |                  |    |    |               |
| Concomitant  medication 21                                                            | X-----------------------------------------------------------------------------------------------------------------------X |                                                                                                                           |                  |    |    |               |
| Inpatient nutrition  assessment (NRS2002)                                                                                       | Assessed as needed                                                                                                        |                                                                                                                           |                  |    |    |               |
| Note:                                                                                 |                                                                                                                           |                                                                                                                           |                  |    |    |               |  
Note:  
1. **Informed consent:** Subjects should sign an informed consent form (ICF) before starting any study-related procedure.  
2. **Demographics:** Age, gender, race and ethnicity.  
3. **Medical history and medication history:** History of all neoplastic diseases, history of all anti-tumor therapies, history of other diseases (within 6 months before enrollment and at present), history of other medications (within 6 weeks before enrollment and at present), family history, surgical history, allergic history, smoking history, history of drug abuse/dependence and history of menstruation and childbearing.  
4. **Hematology:** Red blood cell (RBC) count, white blood cell (WBC) count, absolute monocyte count (ABMONO), platelet (PLT) count, absolute neutrophil count (ANC), absolute lymphocyte count (ABLYMP), basophil count, absolute eosinophil count (ABEOS), absolute reticulocyte count (ABRETIC), neutrophil percentage, hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume and mean corpuscular hemoglobin concentration
(MCHC). Hematology test at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.  
5. **Urinalysis:** Potential of hydrogen (pH), specific gravity, urine RBC, urine WBC, urine glucose, urine bilirubin, urine protein, urobilinogen, urine ketone bodies and urine occult blood. Urinalysis at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.  
7. **Blood biochemistry**:
1) **Liver function**: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH),
γ-glutamyltransferase (GGT), total bilirubin (TBIL), direct bilirubin, total bile acids, albumin (ALB), total protein and globulin (GLO).  
6. **Stool routine**: Color, shape, fecal RBC, fecal WBC, fecal occult blood, fecal choline and fecal bilirubin. Stool routine test at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.  
2) **Renal function:** Urea/urea nitrogen, creatinine, creatinine clearance and uric acid. 3) **Blood lipids:** Total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL) and triglycerides (TG).  
4) **Electrolytes:** Potassium, sodium, chloride, phosphorus, magnesium and calcium.  
5) **Cardiac function:** Creatine kinase (CK) and creatine kinase isozyme (CKI).  
6) Blood **glucose:** Fasting blood glucose (GLU).  
Blood biochemistry test at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.  
8. **Coagulation**: Prothrombin time, activated partial thromboplastin time, fibrinogen quantification and international normalized ratio. Coagulation test at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.  
9. **Vital signs**: Body temperature, blood pressure, heart rate and respiration. For D1 and C1D1, vital signs will be measured within 1 h pre-dose and at 10 h (±1 h) pos t-dose on D1 and C1D1; at other visits, vital signs will be measured according to the visit time window. If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
10. **12-lead ECG:** Measurements will be performed after resting in supine position, and the data (PR, QRS, QT and QTcF) will be recorded. For D1 and C1D1, ECG will be performed within 1 h pre-dose and at 10 h (±1 h) post -dose on D1 and C1D1; for C1D21, ECG will be performed within 0.5 h pre-dose and at 2 h (±15 min), 4 h (±15 min), 6 h (±20 min), 8 h (±30 min) and 24 h (±1 h, pre -dose on C2D1) post-dose on C1D21; at other visits, ECG will be performed according to the visit time window. If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
11. **Physical examination:** Assessments will be performed per organ and system. At screening, a comprehensive physical examination will be performed, including body height, body weight, body mass index (BMI), general condition, nervous system, head and neck, lymph nodes, skin, mucosa, chest, abdomen, four limbs and spine; at other visits, only a simple physical examination will be performed, which includes but is not limited to body weight, BMI, general condition, skin and any abnormal signs of concern at the investigator's discretion.
clinical trial protocol
12. pregnancy-related tests

1) For women of childbearing potential, human chorionic gonadotropin (HCG) will be tested. Blood HCG pregnancy test at screening visit should be completed within 7 days prior to the first dose.  
2) For women ≥40 to <60 years of age and at least 12 months post-menopausal, follicle stimulating hormone, estradiol and luteinizing hormone will be tested; if necessary, anti-Mullerian hormone can be tested additionally. This test will be performed at screening only.  
3) For men and women ≥60 years of age, a pregnancy-related test is not required.  
13. **Echocardiography**: Left ventricular ejection fraction (LVEF). During treatment, echocardiography will be performed at the same frequency with tumor assessment, i.e., echocardiography will be performed at the end of the 1 st cycle, and the time window is ±1 day after the end of t he cycle. After that, echocardiography will be performed every 2 cycles with a time window of ±7 days from the end of every 2 cycles.  
14. **Serum etiology test:** Human immunodeficiency virus antibody (HIV-Ab), hepatitis B surface antigen (HbsAg), hepatitis B virus (HBV)-DNA (as needed), hepatitis C virus antibody (HCV-Ab) and hepatitis C virus (HCV)-RNA (as needed). Serum etiology test at screening visit should be completed within 14 days prior to the first dose.
clinical trial protocol
15. tumor assessment

1) Imaging tests like computed tomography/magnetic resonance imaging (CT/MRI) and other radiological examinations of chest, upper abdomen, lower abdomen, pelvic cavity and other positions will be performed. For patients with suspected or known brain metastasis, a radiological examination must be performed at screening/baseline, and contrast-enhanced MRI is preferred (for those allergic to contrast medium, CT/MRI
plain scan is acceptable). If brain metastasis is confirmed at screening, the frequency of brain CT/MRI in the subsequent cycles should be kept consistent with the tumor assessment frequency specified in the study; if it is confirmed that there is no brain metastasis by brain CT/MRI at screening, brain CT/MRI will be performed for confirmation if brain metastasis is suspected by the investigator later. For patients with bone metastasis symptoms, a bone scan must be performed at screening/baseline, and those with a positive result should receive contrast-enhanced MRI scan at the corresponding position for further confirmation. If bone metastasis is confirmed at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if progression of the pre-existing bone metastasis or new bone metastasis is suspected by the investigator later; if it is confirmed that there is no bone metastasis at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if bone metastasis is suspected by the investigator later. Tumor assessments will be performed according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Tumor markers: During the corresponding visits for imaging tests, 4 mL of peripheral blood will be collected for the detection of tumor biomarkers, such as liver cancer [alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA)], breast cancer [cancer antigen 15-3 (CA15-3)], ovarian cancer and endometrial cancer [carbohydrate antigen 125 (CA125)], prostate cancer [prostate specific antigen (PSA)], lung cancer [cytokeratin 19 fragment (CYFRA21-1)] and pancreatic cancer [carbohydrate antigen 242 (CA242)], which serve as auxiliary efficacy indicators.  
2) If a subject received a CT/MRI or other radiological examinations within 4 weeks prior to the first dose and has not received any anti-tumor therapy since this tumor assessment, and at the investigator's discretion, the tumor assessment can be performed according to RECIST v1.1, this examination result can be used as baseline tumor assessment result (repeated examination is not necessary).  
3) A tumor assessment will be performed at the end of Cycle 1, for which the time window is the end of the cycle ± 1 day. Therea fter, tumor assessments will be performed once every 2 cycles, for which the time window is the end of every 2 cycles ± 7 days [if a subj ect's assessment result is complete response (CR), partial response (PR) or stable disease (SD), the subject can continue the treatment and continue to receive tumor assessments once every 2 cycles].  
4) The radiological confirmation examination of CR or PR should be completed 4-8 weeks after the first evaluation of CR or PR.  
5) For the end of treatment visit (EOT), the investigator will determine whether a tumor assessment is required according to the actual condition. If a tumor assessment has been performed within 2 months prior to EOT, it is not necessary to repeat the tumor assessment at EOT visit.  
6) During the subsequent follow-up visits once every 8 weeks (±7 days) after the last dose, a tumor assessment will be performed for the subjects who are assessed as having no tumor progression in the previous assessment.  
16. **Detection of biomarkers:**
1) Detection of biomarkers in tumor tissues: Subjects' tumor tissue specimens within the past 2 years or fresh tumor tissue specimens can be collected at screening; the specimens can be collected from the primary lesion or metastatic lesions.  
After enrollment, fresh tumor tissue specimens will be collected as much as possible at EOT visit or disease progression; the specimens can be collected from the primary lesion or metastatic lesions (keeping consistent with the lesion source at screening as much as possible).  
2) Detection of biomarkers in blood: fresh blood samples can be collected at screening, during the treatment period (C1D15 visit, C3D21 visit and C5D21 visit) and at EOT visit, 5 mL at each time points, with no more than 5 sampling time points.
clinical trial protocol
17. pk blood sampling

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 singledosing 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.  
18. **Blood sampling for the 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.  
19. **Anti-cancer therapy and survival information after study treatment discontinuation:** During the follow-up period following study treatment discontinuation, the anti-cancer therapy and survival information of all subjects will be recorded.  
20. **Adverse event:** Adverse event are defined as all untoward adverse medical events following the use of the investigational product in subjects of a clinical trial. It is manifested as symptoms, signs, diseases or abnormal laboratory findings, but it does not necessarily have a causal relationship with the investigational product. See Section 8.1.1 of the main text for details.  
All adverse medical events that occur during the period from subject's signing of the ICF to the first dose of the investigational product will be recorded as medical history instead of being recorded as AEs, unless they meet one of the following conditions:
➢ Any adverse medical event related to procedures specified in the clinical study protocol (e.g., bruising caused by blood sampling for laboratory test, etc.);
➢ Adverse medical events caused by treatment discontinuation related to clinical study protocol (e.g., change or discontinuation of prior concomitant medications). See Section 8.1.2 of the main text for details.  
21. **Concomitant medication:** Concomitant medications include any medications other than the study drug (including prescription drugs, over-the-counter drugs, natural extracts, nutritional supplements and traditional Chinese medicines) used by subjects from the start of first dose to 28 days after the last dose of study treatment. Medications used by subjects at screening will be recorded as medication history.
clinical trial protocol
dlt evaluation and single-dosing period

Xb: Twice in Cycle 2, e.g., D14 and D21 of the cycle, with a time window of ±3 days; for Cycles 3 to 5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days.  
Xc: For Cycle 2-5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end o f every 2 cycles, with a time window of
±3 days.  
Xd: Existing laboratory test results within the visit time window are acceptable.  
In addition to the safety test items specified in the protocol, additional safety test items may be measured as necessary.
clinical trial protocol
1. study background 1.1 disease

Malignant tumor is one of the diseases seriously threatening human health in current society. According to the latest *World Cancer Report* released by the World Health Organization (WHO) in February 2020, the number of annual new cancer cases worldwide is expected to increase from 18 million in 2018 to 27 million in 2040, an increase of 50%. Among them, the growth rate of new cancer cases in developing countries is higher than that in developed countries [1]. China, in particular, as a developing country, is faced with an increasingly serious situation of malignant tumors due to the acceleration of industrialization, urbanization and population aging, and the existence of unhealthy lifestyles, environmental pollution and other problems, and the incidence of cancer is on the rise, increasing at an average annual rate of 3% to 5%. The data released by the National Cancer Center in February 2018 showed that there were 3.804 million new cases of malignant tumors in China each year, with an average of more than 10,000 people diagnosed with cancer every day, and 7 diagnosed every minute. Each year, the American Cancer Society estimates the numbers of newcancer cases and deaths in the United States. In 2022, there will be approximately 1,918,030 cancer cases and 609,360 cancer deaths in the United States, the equivalent of about 5250 new cancer cases and 1700 cancer deaths each day [2].  
Malignant tumor is a worldwide problem, and its therapies mainly include surgical resection, radiotherapy, chemotherapy, targeted therapy, and immunotherapy, etc. Traditional anti-tumor drugs are mainly cytotoxic drugs, which lack selectivity in killing cells and are toxic and cause adverse effects. Target-based drugs can effectively inhibit tumor growth while reducing toxicity and adverse effects, and thus are increasingly and extensively applied in clinical practice, and also a hotspot in the current research and development of new drugs [3-5].  
Fibroblast growth factor receptor (FGFR), as a member of the receptor tyrosine kinase family, is involved in the regulation of various biological processes (such as cell proliferation, migration, anti-apoptosis and angiogenesis, etc.) by binding to ligand fibroblast growth factor and activating downstream signaling pathways, and has become an important target in cancer therapy. Currently, most of these studies have focused on fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), and fibroblast growth factor receptor 3 (FGFR3). However, many evidences suggest that fibroblast growth factor receptor 4 (FGFR4) plays an important role in the occurrence of various tumors and resistance to treatment of anti-tumor drugs. Among them, abnormal fibroblast growth factor 19 (FGF19)-FGFR4 signaling pathway has been confirmed to be an oncogenic factor for liver cancer, and multiple FGFR4 inhibitors have entered clinical trials.
clinical trial protocol
1.2 mechanism of action of

FGFR4 is a tyrosine kinase receptor that selectively binds to 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/βcatenin (GSK3β/β-catenin), FGFR4 promotes tumor cell proliferation, promotes epithelialmesenchymal transition (EMT), and inhibits tumor cell apoptosis [6]. 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 [7-9]. 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 (TGF-β) [10]. The abnormal signaling pathway of FGF19-FGFR4 complex has been confirmed to be an oncogenic driver of hepatocellular carcinoma (HCC) [11]. In addition, overexpression of FGF19 can inhibit the generation of sorafenib-induced reactive oxygen species (ROS) in liver cancer cells, downregulate ROS signaling, promote cell survival, and inhibit cell apoptosis, which is one of the mechanisms for sorafenib resistance [12]. 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 [13].
clinical trial protocol
1.3 overview of clinical trials

Currently, FGFR4 inhibitors are under research at home and abroad, including BLU-554 (Fisogatinib) and FGF401 (Roblitinib; EVER4010001) undergoing phase I/II clinical trials, BPI- 43487, SY-4798, HS236, HS-10340, ZSP1241, H3B-6527, ABSK011 and ICP105 undergoing phase I clinical trials, and INCB062079 whose phase I trial has been terminated. See Table 1.  
| Table 1 Study status of FGFR4 inhibitors   |                 |                                                                                                                                                                                                                                                                                                                                                                                                                        |          |     |
|--------------------------------------------|-----------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|-----|
| Product Name                               | Company Name    | Indications                                                                                                                                                                                                                                                                                                                                                                                                            | Research | and |
| development  phase                         |                 |                                                                                                                                                                                                                                                                                                                                                                                                                        |          |     |
| BPI-43487                                  | Betta           | Dose escalation: subjects with advanced solid                                                                                                                                                                                                                                                                                                                                                                          |          |     |
| Capsules                                   | Pharmaceuticals | tumors who have had disease progression after  standard therapy, or are intolerable to or cannot  accept standard therapy, or have no standard  therapy available Dose expansion: subjects with FGF19-amplified,  FGF19-overexpressed, or FGFR4-overexpressed  advanced solid tumors who are no longer suitable  for local therapy with curative intent, have had  disease progression after standard therapy, or that | Phase I  |     |  
| Product Name                                                                                 | Company Name                                                                                                                                                                                                                                                                                                               | Indications                                                                                                                                                                                                                                                                                                                                                                                                                   | Research   | and   |
|----------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|-------|
| development  phase                                                                           |                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                               |            |       |
| are intolerable to or cannot accept standard  therapy, or have no standard therapy available |                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                               |            |       |
| SY-4798 tablets                                                                              | Shouyao Holdings                                                                                                                                                                                                                                                                                                           | Dose escalation: subjects with advanced solid  tumors who have failed to respond to standard  therapy or have no standard therapy regimen  available, or are currently not suitable for  standard therapy Dose expansion: subjects with FGF19 IHC+  advanced solid tumors who have failed to  respond to standard therapy or have no standard  therapy regimen available, or are currently not  suitable for standard therapy | Phase I    |       |
| HS236 capsules                                                                               | Zhejiang Hisun                                                                                                                                                                                                                                                                                                             | Advanced solid tumors that have failed to  respond to standard therapy or have no standard  therapy regimen available, or are currently not  suitable for standard therapy                                                                                                                                                                                                                                                    | Phase I    |       |
| HS-10340                                                                                     | Hansoh/Hengbang                                                                                                                                                                                                                                                                                                            | Advanced solid tumors that have no standard                                                                                                                                                                                                                                                                                                                                                                                   |            |       |
| capsules                                                                                     | therapy available, or are intolerable to standard  therapy                                                                                                                                                                                                                                                                 | Phase I                                                                                                                                                                                                                                                                                                                                                                                                                       |            |       |
| ZSP1241 tablets                                                                              | Guangdong                                                                                                                                                                                                                                                                                                                  | Liver cancer, gastric cancer, bile duct cancer,                                                                                                                                                                                                                                                                                                                                                                               |            |       |
| Zhongsheng                                                                                   | esophageal cancer, colorectal cancer and other  advanced solid tumors that do not respond to, are  intolerable to, are not suitable for, or have no  standard treatment regimen available                                                                                                                                  | Phase I                                                                                                                                                                                                                                                                                                                                                                                                                       |            |       |
| H3B-6527                                                                                     | H3 Biomedicine                                                                                                                                                                                                                                                                                                             | HCC subjects who have previously been treated  with standard therapy at least once (unless  contraindicated)                                                                                                                                                                                                                                                                                                                  | Phase I    |       |
| ABSK011                                                                                      | Abbisko                                                                                                                                                                                                                                                                                                                    | Dose escalation: advanced solid tumors that have                                                                                                                                                                                                                                                                                                                                                                              |            |       |
| Therapeutics                                                                                 | progressed or are intolerable to standard therapy,  or have no standard therapy available Dose expansion: FGF19 expression-positive  advanced HCC subjects who have disease  progression or are intolerable to or refuse to or  cannot accept first-line systemic therapy and are  not suitable for other standard therapy | Phase I                                                                                                                                                                                                                                                                                                                                                                                                                       |            |       |
| ICP-105                                                                                      | Beijing InnoCare                                                                                                                                                                                                                                                                                                           | Solid tumors that have progressed after standard                                                                                                                                                                                                                                                                                                                                                                              | Phase I    |       |  
| Product Name                                                                                                                                                                                                                                                                                                                                            | Company Name                                                                                                                                                                                                                                                                                                                                             | Indications                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Research   | and   |      |                     |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|-------|------|---------------------|
| development  phase                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |            |       |      |                     |
| therapy, are intolerable to standard therapy, or  have no standard therapy available                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |            |       |      |                     |
| INCB062079                                                                                                                                                                                                                                                                                                                                              | Incyte                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Part       | 1:    | HCC, | cholangiocarcinoma, |
| esophageal cancer, nasopharyngeal cancer,  and serous ovarian cancer regardless of  FGF19/FGFR4 status; or other solid  malignant tumors with FGF19/FGFR4  alterations based on local detection  (FGF19/FGFR4 pathway activation  alterations include but are not limited to  FGFR4 amplification, FGFR4 activation  mutation and FGF19 amplification). |                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |            |       |      |                     |
|                                                                                                                                                                                                                                                                                                                                                        | Part 2: Subjects will be enrolled in one of  the following 3 cohorts: Cohort A: HCC with FGF19 amplification. Cohort B: HCC without FGF19  amplification. Cohort C: Cholangiocarcinoma,  esophagus, nasopharyngeal, or serous  ovarian cancer (regardless of  FGF19/FGFR4 status), or other solid  malignancies with confirmed  FGF19/FGFR4 alterations. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |            |       |      |                     |
|                                                                                                                                                                                                                                                                                                                                                        | Progression after prior therapy and either a)  no further effective standard anticancer  therapy is available (including subject  refusal) or b) intolerance to standard  anticancer therapy.                                                                                                                                                            | Phase I                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |            |       |      |                     |
| FGF401                                                                                                                                                                                                                                                                                                                                                  | Novartis                                                                                                                                                                                                                                                                                                                                                 | Phase I monotherapy group: FGFR4 and KLB  expression-positive HCC or other advanced  malignant solid tumors that have progressed after  standard therapy, are intolerable to standard  therapy, or do not have standard therapy  available; Phase I combination group: FGFR4 and KLB  expression-positive advanced HCC subjects who  have been previously treated with first- or  second-line systemic therapy (one of which must  include sorafenib therapy), and is diagnosed to  have disease progression during sorafenib  treatment or treatment discontinuation, or | Phase I/II |       |      |                     |
| (Roblitinib;  EVER4010001)                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |            |       |      |                     |  
| Product Name                                                                                                                                                                                             | Company Name                                                                                                                                                                                                                                                                                                                                | Indications                  | Research   | and   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|------------|-------|
| development  phase                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                             |                              |            |       |
| intolerant to sorafenib treatment; Group 1 in phase II: FGFR4                                                                                                                                            | and                                                                                                                                                                                                                                                                                                                                         | KLB                          |            |       |
| expression-positive advanced HCC patients from  Asian countries who have previously received  sorafenib therapy due to advanced HCC, are  diagnosed with disease progression or intolerant  to sorafenib treatment during sorafenib treatment  or treatment discontinuation. Group 2 in phase II: FGFR4 and KLB  expression-positive advanced HCC patients from  non-Asian countries who have previously  received sorafenib therapy due to advanced  HCC, are diagnosed with disease progression or  intolerant to sorafenib treatment during sorafenib  treatment or after treatment discontinuation, nonAsians. Group 3 in phase II: FGFR4 and KLB  expression-positive patients with other advanced  malignant tumors who have progressed after  standard therapy, are intolerant to standard  therapy, or do not have standard therapy  available (regardless of their geographic  location).                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                             |                              |            |       |
| EverNov                                                                                                                                                                                                  | Phase I: Metastatic locally advanced solid                                                                                                                                                                                                                                                                                                  |                              |            |       |
| Medicines                                                                                                                                                                                                | tumors that do not have effective standard  therapy available or have failed to respond to  standard therapy; Phase II: FGF19-positive metastatic or locally  advanced somatic tumors.                                                                                                                                                      |                              |            |       |
| BLU-554                                                                                                                                                                                                  | Cstone/Blueprint                                                                                                                                                                                                                                                                                                                            | Part 1 dose escalation: HCC; |            |       |
| Medicines                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                             |                              |            |       |
| (Fisogatinib)                                                                                                                                                                                            | Part 2 dose expansion study 1: HCC; Part 3 dose expansion study 2: FGF19 IHC+  HCC without prior TKI treatment; Phase Ib: Unresectable locally advanced or  metastatic HCC that has failed standard systemic  therapy or is not suitable for standard therapy; Phase II: Locally advanced or metastatic HCC  without prior systemic therapy | Phase Ib/II                  |            |       |
| Abbreviations: FGFR4 = fibroblast growth factor receptor 4; FGF19 = fibroblast growth factor 19; HCC =  hepatocellular carcinoma; IHC+ = immunohistochemistry positive; TKI = tyrosine kinase inhibitor. |                                                                                                                                                                                                                                                                                                                                             |                              |            |       |  
So far, no FGFR4 inhibitor has been approved for marketing at home and abroad. The highest development stage of FGFR4 inhibitors is clinical phase II trials. Only FGF401, BLU-554 and H3B-6527 have clinical trial results published. The relevant research results are summarized as follows:
clinical trial protocol
roblitinib (fgf401)

The NCT02325739 study [14] was the first-in-human clinical trial of FGF401, a multicenter, nonrandomized, open-label, monotherapy/combination therapy (PD-1 checkpoint inhibitor PDR001)
phase I/II study. According to the information publicized at https://clinicaltrials.gov, the trial enrolled a total of 172 subjects and aimed to assess the safety, pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity of FGF401 in patients with both FGFR4and KLB-positive advanced cancer patients. **The phase I part** explored the safety and tolerability of FGF401 in fasted and fed states based on the effect of FGF19 signaling pathway on bile acid synthesis. Dose escalation was performed based on a Bayesian hierarchical model, and a total of 8 dose escalation groups were set up (50 mg fasted, 80 mg fasted, 80 mg fed, 120 mg fasted, 120 mg fed, 150 mg fasted, FGF401 80 mg fasted + PDR001 300 mg, FGF401 120 mg fasted + PDR001 300 mg). The dose-toxicity relationship at each dose was assessed, and the primary objective was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The phase I part enrolled a total of 86 subjects, and the finally determined RP2D of FGF401 monotherapy in fasted state was 120 mg, the RP2D of FGF401 monotherapy in fed state was 120 mg, and the RP2D of FGF401 + PDR001 combination therapy was FGF401 120 mg and PDR001 300 mg. The phase II part explored the safety and preliminary efficacy of FGF401 in 3 groups of subjects (Group 1: HCC patients from Asian countries; Group 2: HCC patients from non-Asian countries; Group 3: patients with other malignant solid tumors, regardless of their geographic location). All subjects received FGF401 treatment 120 mg once daily (QD). The phase II part enrolled a total of 86 subjects. The median time to disease progression was 2.6 months in Group 1 and 3.9 months in Group 2, and the objective response rate (ORR) was 0.0% in Group 3. The ORR in the 50 mg fasted, 80 mg fasted, 80 mg fed, 120 mg fasted, 120 mg fed, 150 mg fasted, FGF401 80 mg fasted + PDR001 300 mg, FGF401 120 mg fasted + PDR001 300 mg, Group 1, Group 2 and Group 3 was 0.0%, 16.7%, 20%, 3.8%, 0.0%, 14.3%, 16.7%, 16.7%, 6.7%, 5.6%, and 0.0%, respectively; the disease control rate (DCR) was 18.2 %, 33.3%, 60.0%, 50.0%, 47.4%, 71.4%, 50.0%, 50.0%, 43.3%, 61.1%, and 30.0%, respectively; the incidence of serious adverse events (SAE) was 27.27%, 83.33%, 60.00% 57.69%, 47.37%, 42.86%, 0.00%, 33.33%, 50.00%, 25.00%, and 40.00%, respectively. The incidence of SAEs with FGF401 monotherapy was 43.75%, and the incidence of SAEs with combination therapy was 16.67%. Among them, diarrhea, asthenia, pyrexia, vomiting and nausea were the main adverse events (AEs).
clinical trial protocol
fisogatinib (blu-554)

The NCT02508467 study [15] was the first-in-human clinical trial of BLU-554, a multicenter, nonrandomized, open-label, single-agent, single-arm, phase I study that planned to enroll 150 subjects
(115 subjects had been enrolled as of Oct. 2019) and aimed to assess the safety, tolerability, PK, pharmacodynamics and preliminary antitumor activity of BLU-554 in FGF19 immunohistochemically positive (IHC+) HCC patients. This trial consisted of three parts: (1) Part 1 dose escalation (classical 3+3 design), 140 mg-900 mg; (2) Part 2 dose expansion, RP2D administration; (3) Part 3 dose expansion, patients who had not previously received tyrosine kinase inhibitors (TKIs), RP2D administration. The preliminary phase I results showed that the 600 mg group well tolerated the treatment, and 2 subjects in the 900 mg group experiencing dose-limiting toxicity (DLT). The RP2D was 600 mg QD. The collected safety data showed that most AEs were grade 1 or 2 with manageable adverse effects, with the main AEs being diarrhea, nausea and vomiting. As of Oct. 2019, a total of 98 of the 106 subjects who received the QD dose had undergone efficacy assessment; among the 66 FGF19 IHC+ subjects, 11 (17%) were assessed to have objective response, including 1 (2%) subject with complete response (CR) and 10 (15%) subjects with partial response (PR); the median duration of response (mDOR) was 5.3 months; the median progression-free survival (mPFS) was 3.3 months (2.1-3.7 months). Among 34 subjects with FGF19 IHC-negative or unknown FGF19 status, the ORR was 0.0%. The above efficacy further confirmed the oncogenic driving role of FGF19-FGFR4 signaling pathway in HCC, and further confirmed that FGF19 is a predictive biomarker for precise treatment of HCC.
clinical trial protocol
h3b-6527

The NCT02834780 study [16] was the first-in-human clinical trial of H3B-6527, a multicenter, nonrandomized, open-label, single-agent, single-arm, phase I study that planned to enroll 128 subjects
(128 subjects were enrolled actually) and aimed to assess the safety, tolerability, PK, pharmacodynamics, and preliminary antitumor activity of H3B-6527 in subjects with HCC or intrahepatic cholangiocarcinoma (ICC). The trial used a 3+3 design with dose escalation ranging from 300 to 2000 mg QD or 500 to 700 mg twice daily (BID). So far, 128 subjects have been enrolled in the study, of whom 90 FGF19-positive HCC subjects were treated (48 QD, 42 BID), and ICC subjects (38 subjects have been enrolled actually) were suspended due to limited efficacy. No DLT was observed, and no treatment-related grade 4-5 AEs were observed. Based on the safety, efficacy and PK data, the RP2D of H3B-6527 was 1000 mg QD. In the QD administration group, 12.5% subjects experienced grade 3 AEs, and 62.5% subjects experienced treatment-related AEs, the most common of which were diarrhea (45.8%), asthenia (12.5%), and nausea (12.5%). The incidence of discontinuation due to AEs in the QD administration group was 8.3%. The interim data analysis showed that for HCC subjects who had previously received >2 lines of therapy, the overall survival (OS) of QD administration was 10.6 months, the progression-free survival (PFS) was 4.1 months, the overall response rate was 16.7 % (both PR), and the clinical benefit rate was 45.8% (response + stable disease for >17 weeks). The existing results have shown that H3B-6527 has good tolerability and anti-HCC activity.
clinical trial protocol
other code none

English chemical name: N-(5-cyano-4-((2-methoxyethyl) amino) 56 yridine-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-2,4-methano-1,8-naphthyridine-1(2H)- carboxamide 2-hydroxypropane-1,2,3-tricarboxylate Molecular formula: C26H30N8O4·C6H8O7 Molecular weight: 710.70
clinical trial protocol
stereochemistry none

BB102 is a small molecule FGFR4 inhibitor independently developed by the sponsor. It has the same mechanism of action as BLU-554 and FGF401, and belongs to the innovative drug/molecular. The dosage, route of administration, method of administration and treatment schedule of the investigational product (BB102 tablets) are detailed in Sections 5.2 and 6.2.
clinical trial protocol
1.5 summary of nonclinical studies

Nonclinical studies have shown that BB102, as a novel FGFR4 inhibitor with completely independent intellectual property rights, has a clear mechanism of action, high pharmacodynamic target selectivity, and high activity *in vitro* and *in vivo*, can significantly inhibit the growth of various liver cancer, rhabdomyosarcoma, and breast cancer xenograft models, and has good safety.  
BB102 is expected to be characterized by few adverse effects, low effective dose, and long duration of drug effect in clinical applications. The results of nonclinical studies are detailed in the Investigator's Brochure. This protocol only provides a brief description.