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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):** ORR, DCR, duration of response (DOR), PFS,
and 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-3one), total bile acids, total cholesterol, TG and serum FGF19 protein level in blood.  
**Correlation between plasma concentration of study drug and QTcF (C-QTcF analysis).** **Metabolites of BB102.**
7.2 Expansion Trial Primary endpoints:
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efficacy of bb102 tablets (fasted)

**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-3one), total bile acids, total cholesterol, TG and serum FGF19 protein level in blood.
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8. safety evaluation 8.1 ae

AEs refer to any untoward adverse medical events following the use of the investigational product in subjects. It is manifested as symptoms, signs, diseases or abnormal laboratory findings, but it does not necessarily have a causal relationship with the investigational product.
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other considerations for ae diagnoses

- Each event should be recorded based on a single diagnosis. The accompanying signs
(including abnormal laboratory values or ECG results) or symptoms should not be recorded as additional AEs. If the diagnosis is unknown, the signs or symptoms can be recorded as AEs accordingly.
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laboratory values and ecg results

- Only when judged as clinically significant (i.e., some measures or interventions are required, the change is outside of normal physiological variation range as judged by the investigator), the change of laboratory values or ECG parameters can be regarded as AEs. Repeated laboratory test and/or continuous monitoring of abnormal values are not regarded as intervention. Moreover, repeated or additional non-invasive examination performed to verify, evaluate or monitor abnormality is not regarded as intervention.  
- If abnormal laboratory findings or ECG findings are pathological results of an overall diagnosis (e.g., creatinine increased in renal failure), only the diagnosis should be reported as AE accordingly.
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pre-existing diseases

- Pre-existing conditions should not be recorded as AEs. However, if these concomitant conditions worsen or have complications, such worsening or complications should be recorded as AEs (after administration of the study drug) accordingly.
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change in severity of ae

- If the patient experiences any changes in severity of AEs: (1) when the CTCAE grade is elevated, the AEs should be recorded separately, and the start date of the grade-elevated AE should be the same as the end date of the original AE; (2) when the CTCAE grade is reduced, the AE is not recorded separately, with only the highest CTCAE grade recorded, and the actions taken with the study drug and causal relationship with the study drug all remained as the records of the highest CTCAE grade, but the relevant information should be updated in a timely manner, especially the outcomes and the end date.
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surgeries or procedures

- Surgeries during the study period should be considered as AEs, but operations/therapies  
such as abdominocentesis and thoracocentesis should not be recorded as AEs.
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8.1.2 collection and reporting process

AEs will be collected from the first dose of investigational product to 28 days after the last dose of investigational product or the start of new anti-tumor therapy (whichever occurs first). During the AE collection period, all AEs should be reported in the source medical record and the eCRF. After the AE collection period, only the existing AEs, newly occurred AEs definitely related/possibly related/possibly unrelated to the study drug/ucertain, and AEs leading to death will be recorded. For AEs still existing after the end of study treatment, if they are related to the study treatment, they will all be followed up until resolution, stabilization, death, loss to followup or it is reasonably explained. 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).
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ae reporting

At each study visit, the investigator will assess whether there is a subjective AE. A neutral question can be asked, such as "How do you feel since the last visit?". All clinically significant laboratory abnormalities confirmed by repeated laboratory test will be followed-up until these abnormalities are resolved to acceptable level or satisfactory explanation is given. For all AEs, no matter stated by the subject, asked out by the investigator or found out by physical examination, laboratory test or other methods, they should all be recorded in the source medical records and the eCRF completely no matter regardless of being related to the study drug as considered by the investigator. The following information will be recorded for AEs:
Event term.  
Start and end date. Severity.  
The investigator's judgment on the causal relationship between the AE and the study drug.  
Relevant actions taken with the study drug. Treatment or interventional measures taken for AEs.  
Event outcome.  
SAE or not.
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8.1.3 evaluation of severity

The investigator should grade AEs according to CTCAE v5.0. Note: CTCAE v5.0 is only used for grading of AEs, and it is not used to determine whether the AE is an SAE. Referring to CTCAE v5.0, if there are AEs not listed in the table, they can be classified into 1-5 grades according to the following criteria: Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL (instrumental ADLs refer to preparing meals, shopping for clothes, using the telephone, managing money, etc.). Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling, limiting self-care ADL (self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden). Grade 4: life-threatening; urgent intervention indicated. Grade 5: death related to AEs.
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8.1.4 evaluation of causal relationship

The causal relationship of AEs with the study drug is evaluated as definitely related, possibly related, possibly unrelated, definitely unrelated and uncertain (see Table 3).  
| Table 3 Criteria for evaluation of causal relationship between AE and study drug   |                                                          |                                                                                           |                                |
|------------------------------------------------------------------------------------|----------------------------------------------------------|-------------------------------------------------------------------------------------------|--------------------------------|
| relationship                                                                       | Temporal sequence                                        | Known reaction type                                                                       | Influence of other confounding |
| Causal                                                                             | factors                                                  |                                                                                           |                                |
| There is a rational temporal  relationship between the  AE's occurrence and        | The event meets the  known reaction type  of study drug. | Influence of other confounding  factors such as pre-existing  diseases has been excluded. |                                |
| Definitely  related                                                                |                                                          |                                                                                           |                                |  
| relationship                                                                                                                                                                                                                                                                                | Temporal sequence                                                                                        | Known reaction type                                                                       | Influence of other confounding   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|----------------------------------|
| Causal                                                                                                                                                                                                                                                                                      | factors                                                                                                  |                                                                                           |                                  |
| administration. For example,  the AE will disappear, be  relieved or improved rapidly  after drug withdrawal, which  may recur even aggravate  obviously after resuming the  drug (that is, rechallenge  positive). The event follows a temporal  sequence from the drug's  administration. | The event meets the  known reaction type  of study drug.                                                 | The patient's clinical status or                                                          |                                  |
| other therapies may also give rise  to such event.                                                                                                                                                                                                                                          |                                                                                                          |                                                                                           |                                  |
| Possibly  related                                                                                                                                                                                                                                                                           | The patient's clinical status or                                                                         |                                                                                           |                                  |
| other therapies may also give rise  to such event. Relationship with administration  cannot be ruled out.                                                                                                                                                                                   |                                                                                                          |                                                                                           |                                  |
| The event does not  quite meet the known  reaction type of study  drug.                                                                                                                                                                                                                     |                                                                                                          |                                                                                           |                                  |
| The event does not follow a  temporal sequence from the  drug's administration.                                                                                                                                                                                                             |                                                                                                          |                                                                                           |                                  |
| Possibly  unrelated                                                                                                                                                                                                                                                                         | The patient's clinical status or                                                                         |                                                                                           |                                  |
| other therapies may also give rise  to such event. The event disappears  after the disease status improves or  other treatments are stopped, but  the event reoccurs after repeated  use of other treatments. It is closely  related to other risk factors.                                 |                                                                                                          |                                                                                           |                                  |
| The time of the event does  not follow a temporal  sequence from the drug's  administration.                                                                                                                                                                                                | The event meets the  known reaction type  of non-study drug.                                             |                                                                                           |                                  |
| Definitely  unrelated                                                                                                                                                                                                                                                                       | The occurrence time of the  event has no clear  relationship with the  temporal sequence of  medication. | Use of other drugs may also cause  such event. There is no enough evidence for  judgment. |                                  |
| The event is similar to  the known reaction  type of the study drug.                                                                                                                                                                                                                        |                                                                                                          |                                                                                           |                                  |
| Uncertain                                                                                                                                                                                                                                                                                   |                                                                                                          |                                                                                           |                                  |
| Abbreviation: AE=adverse event.                                                                                                                                                                                                                                                             |                                                                                                          |                                                                                           |                                  |
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8.1.5 study drug-related actions

- **Drug withdrawal:** the study drug is withdrawn due to a specific AE.  
- **Dose unchanged:** study drug does not need to be withdrawn for a specific AE.  
- **Dose reduction:** dose reduction due to a specific AE. - **Dose interruption:** temporary interruption/suspension of the study drug (including the subject's active interruption of the drug) due to a specific AE, and then resume the drug afterwards.  
- **Unknown:** only used when the action taken cannot be determined.  
- **Not applicable:** the study drug is withdrawn due to reasons other than specific AEs, e.g., the study has been terminated, the patient died, the study drug has already been stopped before the onset of the AE.
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8.1.6 outcome of aes

Outcome of AEs can be described as follows:
- **Recovered/resolved, with no sequelae:** the event has been resolved and the patient has no sequelae. "End date of (serious) adverse events" should be indicated.  
- **Recovered/resolved, with sequelae:** the event has been resolved, but the patient has longterm or lifelong sequelae, like hemiplegia caused by stroke. "End date of (serious) adverse events" should be indicated.
- **Recovering/resolving:** the event is not completely resolved, but the patient is recovering.  
Follow-up visits are required.
- **Unrecovered/unresolve**: the event is ongoing. Follow-up visits are required. - **Fatal:** death date should be indicated.  
- **Unknown:** the investigator cannot learn about the AE, e.g., the patient is lost to follow-up.  
If outcome of an AE is determined to be "recovering/resolving" or "unrecovered/unresolved" or "unknown", the end date of the AE may not be recorded temporarily.
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8.2 adr

ADR refers to any harmful or undesirable reactions that may occur in clinical trials and be related to investigational products. There is at least a reasonable possibility of a causal relationship between the investigational product and the AE, i.e., the correlation cannot be ruled out. In this trial, ADRs include AEs that have the causal relationship with the study drug as definitely related, possibly related, possibly unrelated, and uncertain.
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8.3 sae 8.3.1 definition of

SAEs refer to the following medical adverse events occurring after the subject receiving the investigational product:
- Deatha - Being life-threateningb - Hospitalization or prolonged hospitalizationc - Persistent or serious disability or incapacityd - Congenital abnormalities or birth defecte
- Other important medical eventsf
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further explanations for saes are

a. Any death occurring during the study period or within 28 days after the last dose, including those completely unrelated to the study drug. If the patient dies during the study period and an autopsy is conducted, the investigator should provide the sponsor and the Ethics Committee with other necessary information, such as autopsy report and final medical report.  
b. Occurrence of AEs causes immediate risk of death for the patient. These do not include AEs that may cause death after serious progression, e.g., drug induced hepatitis without liver failure.  
c. Any AEs resulting in hospitalization or prolongation of existing hospitalization (prolongation of existing hospitalization means the planned or expected discharge is delayed, usually after staying overnight in the hospital for at least one day). These do not include elective surgeries or examination before admission decided before the study, with no change of treatment course during the study.  
d. Any AEs causing injury, damage or destruction of patient's function and/or physiological structure, physical activity or quality of life.  
e. It is suspected that exposure of parent to the study drug may cause adverse outcome of descendants.  
f. Medical and scientific judgment must be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may be considered serious if medical intervention is necessary to prevent one of the above situations. For example, intensive therapy in the emergency room or allergic bronchospasm at home, blood dyscrasia or convulsion not resulting in inpatient hospitalization, or those leading to drug dependence or drug abuse.
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death

All death events that occur during administration period or within 28 days after the last dose must be reported to the sponsor/CRO's safety department within 24 hours, and the death causes should be recorded in proper areas in the eCRF and the SAE report. If the death is jointly caused by multiple reasons, the investigator must determine the main cause of the death. The report should include information on AE condition, major or minor causes of death (if any), etc. In case of reports involving death events, the investigator should provide the sponsor/CRO and the Ethics Committee with other necessary information, such as autopsy report and final medical report. Note: Generally, disease progression (including progressive symptoms and signs) should not be reported as an AE or SAE, but it should be reported as an SAE (with the severity as grade 5) if the patient's death is due to his/her disease progression (and the death can not be included as any of the grade 5 AEs in CTCAE).
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hospitalization

AEs requiring hospitalization for treatment are considered as SAEs. In general, hospitalization includes admission and treatment. Hospitalization does not include the followings:
- Rehabilitation facility;  
- Nursing home;
- Admission to routine emergency room;
- Surgeries on the same day (e.g., outpatient/same day/ambulatory procedures);
- Unnecessary hospitalization and treatment (e.g., hospitalization for the reason of medical insurance reimbursement).
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8.3.2 collection and reporting of

Except for the SAEs unnecessary to be reported immediately as per the trial protocol or other documents (e.g., Investigator's Brochure), the investigator should report all the SAEs to the Sponsor/CRO in writing immediately, and thereafter provide a detailed and written follow-up report in a timely manner. For any SAE in the trial, regardless of whether it is related to the study drug or not, the investigator should provide timely rescue treatment, complete the *Serious Adverse Event Reporting Form* within 24 hours of awareness, sign and date it and report it to the sponsor/CRO. For initial SAE report, the investigator should record in detail about the report source, basic information of the subject, name of the study drug, SAE name, SAE symptoms/vital signs/examination indicators, start and end date, severity, treatment time, actions taken, causal relationship with the study drug and outcomes, etc., and ensure that the record is true, accurate, complete, timely and legal. After the initial report, the SAE should be continuously followed up and relevant new information or updated information of the previous report should be reported in the form of follow-up report timely (the follow-up report should be reported within 24 hours after obtaining the new information). The investigator must provide causality assessment when reporting SAEs. If the investigator can not confirm whether the AE is an SAE, it will be considered as an SAE before proving its nature.
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8.5 adverse events of special

In the expansion trial, AEs meet the DLT definition in Section 4.1.1.4 are considered as AESIs.
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8.6 suspected unexpected serious adverse

SUSARs refer suspected unexpected serious ADRs whose clinical manifestations are beyond the Investigator's Brochure for the investigational drug, package inserts for marketed drugs, summary of product characteristics and other existing information in terms of their nature and severity. After receiving safety-related information from any source, the sponsor should immediately analyze and assess, including the severity, causality with the investigational drug, and whether it is an expected event. The sponsor should report SUSARs to all participating investigators, clinical trial institutions and Ethics Committees in an expedited manner; the sponsor should report SUSARs to drug regulatory authorities and health authorities. After receiving the relevant safety information of the clinical trial provided by the sponsor, the investigator should sign and read it in time, and consider whether to make corresponding adjustments to the treatment of the subject. If necessary, the investigator should communicate with the subject as soon as possible, and report SUSAR provided by the sponsor to the Ethics Committee. In addition, the sponsor should make an expedited reporting of SUSARs to the center for drug evaluation (CDE) in a manner of individual case safety report (ICSR)according to *Criteria and* Procedures for Expedited Reporting of Safety Data During Drug Clinical Trial Issued by CDE on April 2018. For SUSARs, if the sponsor and the investigator can't agree on the causal relationship between the AE and the drug and any party considers that it is unable to exclude the correlation, expedited reporting should also be carried out.
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the time limit for expedited

(I) For fatal or life-threatening SUSARs, the sponsor should report them as soon as possible and not more than 7 days after the first awareness, and should report and improve the follow-up information within the next 8 days. Note: The day of the sponsor's first awareness is Day 0.  
(II) For non-fatal or life-threatening SUSARs, the sponsor should report them as soon as possible and not more than 15 days after the first awareness of the event. After the initial report, the sponsor should continue following up the event and report relevant new information or update the previous report in the form of follow-up report timely (within 15 days after obtaining the new information).
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8.7 pregnancy

Pregnancy itself is not an AE or SAE. However, if the outcome of the pregnancy meets SAE criteria (e.g., spontaneous abortion, stillbirth, death neonatal, congenital anomaly or birth defect), the corresponding event should be reported as an SAE. For the contraceptive measures, definitions of child-bearing potential women, and contraceptive requirements, see Appendix III.
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female subjects become pregnant

If female subjects are found pregnant during the study (from the start of administration to within 3 months after the last dose), the investigator should complete Pregnancy Reporting Form within 24 hours of awareness, report to the sponsor/CRO in an expedited manner, record it in the source medical records and the eCRF, and follow up the outcome of pregnancy (e.g., normal birth, preterm labour, spontaneous abortion, induced abortion, death neonatal, congenital anomaly or birth defect, etc.). The investigator should propose advice to the subjects and discuss the risks of continuing pregnancy and the possible effects on the fetus. The subjects should terminate the study drug and withdraw from the study, and they should be monitored continuously until the end of pregnancy.
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female partners of male subjects

If the female partners of male subjects are found pregnant during the study (from the start of administration to within 3 months after the last dose), the investigator should complete Pregnancy Reporting Form within 24 hours of awareness, report to the sponsor/CRO in an expedited manner, record it in the source medical records and the eCRF. Under the permission of the study site, the pregnant partner should sign an authorization form of the use and release of pregnancy health information to allow the follow-up for the outcomes of their pregnancy (e.g., normal birth, preterm labour, spontaneous abortion, induced abortion, stillbirth, death neonatal, congenital anomaly or birth defect, etc.). The investigator should propose advice to the subjects and their female partners and discuss the risks of continuing pregnancy and the possible effects on the fetus. The male subjects are not required to discontinue the study drug or withdraw from this study, however, their female partners should be monitored until the end of pregnancy.
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9. data management

See the data management plan for detailed data management methods, e.g., collection and management procedures of trial data, system used for data collection and management, steps and tasks of data management, and quality assurance measures for data management.
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9.1 completion and transfer of

1) The investigator should supervise the data collection and the responsibility implementation of all trial staff at the study site.  
2) The investigator should ensure that all clinical trial data are obtained from clinical trial source files and trial records, and are accurate, complete, readable and timely. Source data should be attributable, legible, contemporaneous, original, accurate, complete, consistent and enduring. In case of any amendment to source data, it should be marked, rather than being covered up, and the reasons for such amendment should be recorded. In the trial, relevant medical records should be entered into the outpatient service system or the inpatient record system. When the information-based system of the clinical trial institution manages to establish the electronic medical record of clinical trials, the investigator should give preference to such system, which should be equipped with perfect permission management and audit trail, be able to date back to the record creator or modifier, and ensure the traceability of all the source data collected.  
3) The investigator should complete and modify the eCRF in accordance with the instructions provided by the sponsor and ensure that the data in various eCRFs and other reports is accurate, complete, clear and timely. The data in the eCRF should be consistent with the source documents. If there is any inconsistency, a reasonable explanation should be made. Modification of data in the eCRF should keep the initial record clear and legible and modification trail should be kept. Reasons should be given when necessary and the modifier should sign and date.  
The sponsor should have written procedures to ensure that their changes to eCRF are necessary, recorded, and approved by the investigator. The investigator should keep records of revisions and corrections.
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9.2 database design

The Data Department of the CRO is responsible for data management of this study, and an electronic data capture (EDC) system is used to ensure the authenticity, integrity, privacy and traceability of the clinical study data. The eCRF database is established by Data Department of CRO in the system in accordance with the requirements of Food Drug Administration 21 CFR Part 11. The database allows management of data traces such as system logins, data entry, modification and deletion, etc. The database will be established according to the standards developed by the Clinical Data Interchange Standards Consortium as far as possible.
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9.3 data entry

In accordance with the corresponding SOP, the investigator or personnel authorized by the investigator entered the information to the EDC system in a timely manner after the completion of visits strictly according to principle of "input what you see". After the data are entered, any correction to eCRF will be automatically recorded in the system.
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9.4 data verification

Data manager (DM) will set logic verification program in EDC system according to the final data verification plan. After the data are entered into EDC system, if there is any data not conforming to logic, the system verification will be initiated and trigger data queries. These inquiries have to be reviewed and responded by the investigator or the person authorized by the investigator. If updated data makes logic verification no longer valid, data inquiry will be closed immediately; if the study site confirms data and provides response, DM should review the response. If the reason is acceptable, the data inquiry will be closed; if data problem is not resolved, DM can continue adding data inquiry to communicate with the study site until final resolution. Subject data listings/reports will be generated through programming to support manual data verification throughout the study. If data has to be clarified/verified/confirmed by the investigator, manual inquiry can be added in EDC system. DM should ensure that all queries are resolved before database lock and the investigator completes electronic signature in EDC system to ensure the integrity and accuracy of subject data in the EDC system.
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9.5 medical coding

DM in Data Management of CRO are responsible for medical coding of this study. Coding contents include past medical history, AEs, and concomitant medications. 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 WHO Drug Dictionaries (current version or updated version). During the coding process, if the data cannot be coded due to inappropriate, inaccurate, ambiguous medical terms, DM will ask the investigator to check and confirm it in the manner of data queries. Before database lock, DM will send medical coding report to the sponsor for review.
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9.6 database locking and unlocking

After the review is completed and the established database is confirmed to be correct, the principal investigator, sponsor, DM, and statistician will jointly lock the data. In principle, any changes to the locked database are not allowed. If unlocking is required, the application will be jointly signed and submitted by the principal investigator, DM, statisticians and other personnel. The re-locking of the database should follow the same process as the first locking of the database.
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10. statistical analysis 10.1 sample

This trial is a phase I clinical trial and does not estimate the sample size.  
This trial plans to enroll 31-78 subjects in total:
➢ It is expected that the dose escalation trial will enroll 19-42 subjects; ➢ It is expected that the expansion trial will enroll 12-36 subjects.
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10.2 statistical analysis set

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 concentrationtime 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.
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10.3 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 nonmissing subjects. If necessary, the two-sided 95% confidence interval (95% CI) for the percentage
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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 MedDRA (current or updated version). Previous medications and concurrent/concomitant medications will be coded according to the WHO Drug Dictionaries (current version 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.
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10.4 statistical methods 10.4.1 subject

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.
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10.4.2 analysis of demographics and

The demographic data and baseline characteristics will be descriptively summarized, including gender, age, race, ethnicity, body height, BMI, past 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.
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10.4.3 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.
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10.4.4 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 postdose (regardless of the clinically significance) will be listed.
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10.4.5 dlt analysis

Number of subjects with DLT as well as the category, severity and incidence of DLT will be summarized.
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10.4.6 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.
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10.4.7 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 AUC0t) 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.
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10.4.8 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
≥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 two-sided 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 two-sided 95% CI, and survival curves will be drawn.  
| Estimated objective: Population:   | FGF19 or FGFR4 positive advanced primary HCC or other advanced solid  tumors   |     |    |                                                                    |
|------------------------------------|--------------------------------------------------------------------------------|-----|----|--------------------------------------------------------------------|
| Treatment:                         | See Section 6 for details                                                      |     |    |                                                                    |
| Endpoint:                          | ORR                                                                            |     |    |                                                                    |
| Intercurrent                       | events                                                                         | and | -  | Discontinuation of study treatment or initiation of new anticancer |
| handling strategies:               | therapy prior to CR or PR will be handled according to the while-ontreatment strategy.                                                                                |     |    |                                                                    |
| Summary at the population          | ORR and corresponding two-sided 95%CI (estimated by Clopper-Pearson            |     |    |                                                                    |
| level:                             | method) will be calculated                                                     |     |    |                                                                    |  
| Estimated objective: Population:   | FGF19 or FGFR4 positive advanced primary HCC or other advanced solid  tumors                                   |     |    |                                                                    |
|------------------------------------|----------------------------------------------------------------------------------------------------------------|-----|----|--------------------------------------------------------------------|
| Treatment:                         | See Section 6 for details                                                                                      |     |    |                                                                    |
| Endpoint:                          | DOR                                                                                                            |     |    |                                                                    |
| Intercurrent                       | events                                                                                                         | and | -  | Discontinuation of study treatment or initiation of new anticancer |
| handling strategies:               | therapy prior to objective tumor progression or death will be handled  according to the hypothetical strategy. |     |    |                                                                    |
| Summary at the population          | The variables of event time will be descriptively summarized, and KM                                           |     |    |                                                                    |
| level:                             | curves will be plotted                                                                                         |     |    |                                                                    |  
For other efficacy measures (DCR, PFS and OS), an estimation method like that of ORR or DOR will be used.
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10.4.9 biomarker analysis

The relationship between biomarker and efficacy will be analyzed, and the correlation will be inferred preliminarily.
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10.4.10 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.
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10.4.11 metabolite analysis

Metabolites of BB102 will be identified. The metabolites and subjects will be tabulated.  
10.4.12 **Subgroup analysis**
Subgroup analysis will be performed by gender.  
10.4.13 **Interim analysis**
Not applicable.
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11. trial management 11.1 statement

The clinical trial should be implemented in accordance with the ethical principles of *Declaration* of Helsinki, GCP and relevant regulations on drug clinical trials. By signing the protocol, the investigator agrees to comply with the instructions and procedures set forth in the protocol, and to comply with the principles of GCP and all local regulations and medical research.
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11.2 ethical considerations

The investigator must submit the trial documents to the Ethics Committee of the study site for review and approval, and the Ethics Committee should deliver its approval comments to the investigator in a written form. Before drug shipment to the investigator, a copy of approval letter from the Ethics Committee and a checklist of reviewed documents must be submitted to the sponsor. The Ethics Committee's approval letter should clearly list all the committee members involved in the review with their respective responsibilities. After the Ethics Committee has approved the study protocol, the sponsor/CRO should register it on the clinical trial registration platform (e.g., https://www.clinicaltrials.gov/). Amendments of study protocol must be submitted to the Ethics Committee for review and approval, and reported to drug regulatory authorities according to local requirements. In case of reports involving death events, the investigator should provide the sponsor and Ethics Committee with other necessary information, such as autopsy report and final medical report. The Ethics Committee should be informed of the end of study data collection.
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11.3 source data verification

The investigator must properly handle all data obtained during the clinical study period and guarantee the rights and privacy of subjects participating in this clinical study. Monitoring refers to the activities to oversee the progress of a clinical trial and ensure that the clinical trial is performed, recorded and reported as per its trial protocol, SOP and applicable laws and regulations. The sponsor assigns certain monitor to perform regular monitoring to the clinical trial. According to the SOP, the monitor should confirm that the clinical study-related activities are in compliance with regulations, and confirm the certificate and resource of clinical trials, and verify the consistency of eCRF, source data and other relevant documents, and write monitoring report. Audit refers to a type of systematic and independent inspection against relevant activities and documents of a clinical trial. The purpose of an audit is to determine whether the implementation of the trial, the recording, analysis and reporting of data comply with the protocol, SOP and relevant laws and regulations. The sponsor should assign the personnel independent to the clinical trial, not the monitor, as the auditor. The auditor audits the clinical trial to evaluate whether trialrelated activities and records comply with the trial protocol, SOP and relevant laws and regulations on drug clinical trials, and writes the audit report. Inspection refers to the act by drug regulatory authority in conducting a review of documents, facilities, records and other aspects of a clinical trial. Inspection can be done on the study site, or at the location of the sponsor or the CRO, or any other places considered by the drug regulatory authority as essential. The drug regulatory department may carry out official review and inspection on relevant documents, facilities, records and other aspects of clinical trials. The drug regulatory authority can ask the sponsor to provide audit reports as required by work. The investigator must allow the monitors/auditors/inspectors to review and check the required clinical study documents so as to verify the accuracy of the source data and understand the progress of this study. If the source data cannot be verified, the investigator should agree to assist the monitors/auditors/inspectors in the further confirmation of data quality control.
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11.4 quality assurance

All drugs and materials used in all clinical studies must be on the premise of quality control. The sponsor, personnel authorized by the sponsor or related medical regulatory authorities have the right to review the clinical study in order to ensure the authenticity of the clinical study data and compliance with the provisions of the clinical study protocol. The monitor/auditor/inspector have access to all medical records, study-related documents and correspondences, and the informed consent documents of this clinical trial. The participants of clinical study will be informed of such clinical study reviewing process, but the privacy and data materials of participants will be strictly protected.
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11.4.1 requirements for sponsor

The sponsor is responsible for providing trial fees and Investigator's Brochure. The contents of the Investigator's Brochure include chemical, pharmaceutical, toxicological, pharmacological and clinical (prior and ongoing trials) documents and data. The study protocol and completion rules of eCRF will be well explained to investigators before the initiation of the clinical trial. The sponsor must provide the investigator with study drugs with easily identified and accurate code and special labeling and ensure qualified quality. The communication methods and monitoring methods should be monitored for AEs between the sponsor and the study site to ensure that the investigator can be kept in touch at any time via telephone, fax or email. The sponsor should designate the monitor to conduct clinical trial monitoring and timely written reporting in accordance with this protocol, monitoring plan and monitoring-related SOPs, and make sure that the clinical trial is carried out and recorded correctly as per the trial protocol. The sponsor should review and follow up on the problems in the monitoring report, and keep them in the form of a document.
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11.4.2 requirements for investigators

The investigator should carry out this trial in compliance with the requirements of the clinical protocol, GCP and relevant laws and regulations. The investigators must make sure that the conduct of the study is completely in compliance with the ethical principles of the Declaration of Helsinki and relevant laws and regulations, so as to protect the rights and interests of the subject and guarantee their safety. This protocol should be reviewed and approved by the Ethics Committee of the Study Site prior to implementation. Any revisions of this protocol during the study period must also be approved by the Ethics Committee. The investigator is responsible for obtaining the ICF signed by each subject or his/her legal guardian or impartial witness. The investigator is responsible for guaranteeing that the processes of the receipt, storage, distribution, usage, and returning of study drugs are in compliance with the trial protocol and relevant laws and regulations, and making sure that all used and unused study drugs are managed by documentation, and all drug supplies and relevant records should be monitored and confirmed by the monitor. During the clinical trial, the investigator should accept the monitoring or auditing of the clinical research associate and auditor dispatched by the sponsor as well as the inspection of the drug regulatory authorities to ensure the quality of the clinical trial. The investigator is responsible for writing the summary report, and can publish papers only after permission by the sponsor.
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11.4.3 statistical analysis

The statistical analysis plan is written by the statistical analysis institution based on the Guidelines for Drug Clinical Trial Data Management and Statistical Analysis Plan, Guidelines for Biostatistics of Drug Clinical Trial, GCP and other relevant guidelines, and it is finalized after review. After that, the statistical work is carried out according to the finalized statistical analysis plan and the current SOPs, and the process of data processing will be rechecked.
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11.5 informed consent

ICF should be in compliance with the ethical principles of the *Declaration of Helsinki*, as well as the rules and guidelines formulated by drug regulatory authorities. Signed ICF must be obtained from the subject before the initiation of any clinical trial-related procedures. The investigator should be responsible for the process of informed consent. Before the screening, the investigator is responsible for explaining study objective, methods, benefits and potential risks, other alternative treatments and subjects' rights and obligations consistent with Declaration of Helsinki to each subject; make them understand that they are free to withdraw from the trial at any time while their personnel interests will not be impaired. Before signing the ICF, the investigator or the personnel designated by the investigator should give enough time and chance to the subject or his/her guardian to understand the details of the clinical trial, and answer the questions about the clinical trial raised by the subject or his/her guardian. The process of informed consent should be documented in the disease course records at the day of screening visit. The verbal explanation must be given when the written informed consent form is provided for participants. The informed consent form must be dated and signed by each subject or his/her legal guardian or impartial witness. The subject will keep one copy of the signed ICF, and the other copy will be kept in the investigator site file. If any information related to the subject's willingness to continue participating in the trial is available during the trial, the written ICF must be updated and provided to the subject to confirm if the subject is willing to continue. Note: The approval of Ethics Committee should be obtained for the revised ICF before providing to subjects. By signing the ICF, the subject should agree that the Ethics Committee, drug approval regulatory authorities, sponsor, auditors and/or the sponsor-authorized clinical trial monitors are allowed to check the available source data related to clinical study, and the reviewer must follow confidential statement.
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11.6 trial protocol revision rules

Necessary modifications of the study protocol will be made based on available clinical trial data.  
Investigators shall not revise the trial protocol without the approval of the sponsor and the Ethics Committee, except when necessary to eliminate immediate hazards to the subjects or when the change involves only management of the clinical trial (e.g., change of monitor or telephone number). The investigator should timely report the revision of the trial protocol to eliminate immediate hazards to the subjects without the approval of the Ethics Committee to the Ethics Committee and the sponsor and provide reasons, and if necessary, report to drug regulatory authorities. "Protocol amendment history" should be written when the protocol is modified.
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11.7 ecrf

DM of CRO will establish eCRF in the system. The eCRF only uses appropriate identification codes (e.g., subject screening number) to identify different subjects. Only the data of one subject will be recorded in each eCRF. The eCRF is used for the documentation of clinical study data of subjects, and is a component of this study and relevant study reports. Entry must be therefore accurate and complete. The eCRF is entered by the investigator or an authorized person (should be specified in study authorization form). It must be ensured that all data entry is completed and stored. The investigator must provide an electronic signature to declare that all information in the eCRF is true and correct. In a clinical study, eCRF should be completed as soon as possible after each visit to record the condition of subjects. If the information is not applicable, "NA" should be filled in; if the test item is not done, "ND" should be filled in.
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11.8 monitoring

The monitors designated by the sponsor should conduct clinical trial monitoring and timely submit written reports in accordance with this protocol, monitoring plan and monitoring-related SOPs, and make sure that the clinical trial is carried out and recorded correctly as per the trial protocol. The sponsor should review and follow up on the problems in the monitoring report, and keep them in the form of a document.
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11.9 confidentiality and privacy of

In the process of processing the information of the clinical trial and the subjects, illegal or unauthorized access to, disclosure, dissemination, modification, damage, and loss of information should be avoided. The confidentiality of records and subject information should be guaranteed during the recording, processing and preservation of clinical trial data. The trial staff must safeguard the privacy of subjects. Name of the subjects should not be indicated in all of the documents submitted to the sponsor. The investigator must keep the name, address and enrollment form of the subjects properly. The enrollment form is maintained by the investigator with strict confidentiality and should not be submitted to the sponsor.
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11.10 others 11.10.1 protocol deviations

The investigator should conduct this trial according to the clinical study protocol approved by the Ethics Committee and GCP regulations. The investigator must not revise or deviate from the trial protocol without the approval of the sponsor and the Ethics Committee, except when necessary to eliminate immediate hazards to the subjects or when the change involves only management of the trial (e.g., change of monitor or telephone number). The investigator should timely report the trial protocol deviation to eliminate immediate hazards to the subjects without the approval of the Ethics Committee to the Ethics Committee and the sponsor and provide reasons, and if necessary, report to drug regulatory
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authorities.

The investigator or the personnel designated by the investigator should record and explain trial protocol deviation. The record contents include but are not limited to the occurrence time, time of awareness, event description of and actions taken for the protocol deviation. In case of a significant protocol deviation, the clinical research associate and Ethics Committee should be notified in a timely manner. If necessary, the sponsor can terminate this trial in advance.
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11.10.2 personnel training

All study-related personnel (doctors, nurses and other personnel) authorized by the investigator should accept relevant trainings, and the training records should be kept and archived,
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11.10.3 curriculum vitae of clinical

All clinical investigators participating this trial or other related personnel should provide recent (within 2 years) curriculum vitae to the sponsor to be filed as related documents.
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11.10.4 qualification certificates of clinical

The clinical study site should provide the sponsor/CRO with copies of qualification certificates of the clinical laboratory and the range of normal values to be filed as related documents.
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11.10.5 agreement of clinical study

Before the initiation of the study, the principal investigator must sign the clinical trial protocol to confirm that he/she has well understood the protocol and will conduct the clinical trial in strictly accordance with the protocol.
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11.10.6 insurance

For consideration of subject's safety, the sponsor will buy relevant liability insurance for this study.  
If the subject experiences health injury related to this trial, after being verified by a legal department or institution, relevant medical cost and corresponding financial compensation will be provided according to GCP and applicable national laws and policies.
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12. intellectual property rights and

All information obtained from the trial sponsor belongs to the intellectual property rights of the trial sponsor. Therefore, the clinical trial investigator and all other relevant personnel must strictly keep it confidential, and should not disclose it to any third party without the prior consent of the trial sponsor. The study results are proprietary to the sponsor. The investigator must negotiate with the sponsor before publishing any collected or generated trial-related information. The investigator should guarantee that he/she will not publish on journals or magazines or release on academic or commercial conferences about any content related to the study and/or study results without the written permission from the sponsor. The sponsor has the right of final decision about the manuscript and publication. At the same time, the investigator should understand that the sponsor will not refuse the publication without any reason after being communicated. In order to prevent from unconscious leakage of confidential information or unprotected inventions, the investigator must inform the sponsor in advance to discuss or review together about publications planned to be published or releases of other forms (the forms of publication/release include but are not limited to journal articles, posters, guest lectures). The investigator should provide the sponsor with the original manuscript, abstract or full text planned to be published/released at least 45 days before submitting for publication/release, and the sponsor will check for laws and regulations and intellectual property rights about the contents to be published. If it is for protection of intellectual property rights, especially before the achievement of corresponding patent, the investigator should agree to delay or cancel publication. Prior to publication, the investigator can be asked to delete any confidential information that has not been published before. Many study sites are participating in this study, unless prior consent has been obtained from the sponsor, individual should not publish any data related to the clinical study before the final report of the multi-center study has been completed. The investigator should agree that the first publication is the overall achievement of all study sites. However, if the original manuscript of overall analysis has not been submitted and published within 12 months after the completion or termination of study in all study sites, the investigator may request to publish study results of single site, but the sponsor should still be informed in advance and discussed with. The investigator should not use the name of the sponsor and/or its designator in advertisements or advertising materials and publications before obtaining the written permission from the sponsor. At the same time, the sponsor should not use the name of the investigator in advertisements or advertising materials or publications before obtaining the written permission from the investigator and/or cooperator. As required by the GCP, the contract signed by the sponsor and the investigator should include the agreements about publishing articles and intellectual property rights, etc. **Note: If the description** about publishing articles and intellectual property rights is different from the contract, the contract shall prevail.
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13. clinical data archiving

The sponsor, investigator and clinical trial institution should keep trial documents properly in accordance with the "essential documents for clinical trials" and relevant requirements of drug regulatory authorities. Essential documents: documents, solely or together, to evaluate the implementation process of the clinical trial and the quality of the clinical data. According to the requirements of GCP, for clinical trials that are used to apply for drug registration, the essential documents should be kept for at least 5 years after the investigational drug has been approved for marketing; for clinical trials that are not used to apply for drug registration, the essential documents should be kept for at least 5 years after the termination of clinical trials. If the sponsor wishes to retain for a longer period of time, the retention time and methods will be discussed and decided by all three parties. It is the responsibility of the sponsor to inform the investigator/clinical trial institution of when it is no longer necessary to further retain such data. If the investigator/clinical trial institution makes any changes in document retention, the personnel or investigator responsible for document retention should contact the sponsor. The sponsor should clarify with the investigator and the clinical trial institution about the retention time, fees and processing after expiration in the contract.
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14. references

[1] Dajun D. World Cancer Report 2020 Comes Out-Adjusting cancer prevention strategies to adapt to the new trend of cancer epidemic [J]. J Multidiscip Cancer Manag. 2020, 6(3):2732.  
[2] Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022 [J]. CA: A Cancer Clin. 2022, 72(1).
[3] Rybarczyk-Kasiuchnicz A, Ramlau R. Current views on molecularly targeted therapy for lung cancer - a review of literature from the last five years [J]. Kardiochir Torakochirurgia Pol. 2018, 15(2): 119-124.  
[4] Hsu WH, Yang JC, Mok TS, et al. Overview of current systemic management of EGFRmutant NSCLC [J]. Ann Oncol. 2018, 29(suppl_1):i3-i9.
[5] Daaboul N, Nicholas G, Laurie SA. Algorithm for the treatment of advanced or metastatic squamous non-small-cell lung cancer: an evidence-based overview [J]. Curr Oncol. 2018, 25(Suppl 1):S77-S85.  
[6] Vainikka S, Joukov V, Wennstrom S, et al. Signal transduction by fibroblast growth factor receptor-4 (FGFR-4) -comparison with FGFR-1 [J]. J Biol Chem, 1994, 269:18320-18326.  
[7] Wu AL, Coulter S, Liddle C, et al. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways [J]. PLoS One, 2011, 6:e17868.  
[8] Zhou M, Yang H, Learned RM, et al. Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis [J]. Nat Commun, 2017, 16:15433.  
[9] Urtasun R, Latasa MU, Demartid MI, et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/Yes-associated protein-mediated activation [J]. Hepatology, 2011, 54:2149-2158.  
[10] Huang J, Qiu M, Wan L, et al. TGF-β1 promotes hepatocellular carcinoma invasion and metastasis via ERK pathway-mediated FGFR4 expression [J]. Cell Physiol Biochem, 2018, 45:1690-1699.  
[11] Repana D, Ross P. Targeting FGF19/FGFR4 pathway: a novel therapeutic strategy for hepatocellular carcinoma [J]. Diseases, 2015, 3:294-305.  
[12] Gao L, Wang X, Tang Y, et al. FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib [J]. J Exp Clin Cancer Res, 2017, 36:8.  
[13] Lu X, Chen H, Patterson AV, et al. Fibroblast growth factor receptor 4 (FGFR4) selective inhibitors as hepatocellular carcinoma therapy: advances and prospects [J]. J Med Chem, 2019, 62:2905-2915.  
[14] https://clinicaltrials.gov/ct2/show/NCT02325739?term=NCT02325739&draw=2&rank=1 [15] Kim RD, Sarker D, Meyer T, et al. First-in-Human Phase I Study of Fisogatinib (BLU-554)
Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma [J]. Cancer Discov. 2019, 9(12):1646-1649.  
[16] Macarulla Mercade T, Moreno V, John B, et al. Phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). J Clin Oncol 39, 2021 (suppl 15; abstr 4090).
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15. appendix appendix i recist

This guideline describes a standard approach to solid tumour measurement and definitions for objective assessment of change in tumour size for use in adult and paediatric cancer clinical trials. It is expected these criteria will be useful in all trials where objective response is the primary study endpoint, as well as in trials where assessment of stable disease, tumour progression or time to progression analyses are undertaken, since all of these outcome measures are based on an assessment of anatomical tumour burden and its change on study. There are no assumptions in this appendix about the proportion of patients meeting the criteria for any of these endpoints which will signal that an agent or treatment regimen is active: those definitions are dependent on type of cancer in which a trial is being undertaken and the specific agent(s) under study. Protocols must include appropriate statistical sections which define the efficacy parameters upon which the trial sample size and decision criteria are based. In addition to providing definitions and criteria for assessment of tumour response, this appendix also makes recommendations regarding standard reporting of the results of trials that utilise tumour response as an endpoint. While these guidelines may be applied in malignant brain tumour studies, there are also separate criteria published for response assessment in that setting. This appendix is not intended for use for studies of malignant lymphoma since international guidelines for response assessment in lymphoma are published separately. Finally, many oncologists in their daily clinical practice follow their patients' malignant disease by means of repeated imaging studies and make decisions about continued therapy on the basis of both objective and symptomatic criteria. It is not intended that these RECIST guidelines play a role in that decision making, except if determined appropriate by the treating oncologist.
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i. measurability of tumour at

At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as follows.
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(1) measurable lesions/lymph nodes

Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:
10 mm by CT scan (CT scan slice thickness no greater than 5 mm); 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable);
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20mm by chest x-ray.

Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness should be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
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(2) non-measurable lesions/lymph nodes

All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 mm to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-measurable include: pathologically determined meningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.
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(3) special considerations regarding lesion

Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular comment:
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bone lesions

PET scan or plain films are not considered adequate imaging techniques to measure bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable lesions if the soft tissue component meets the definition of measurability described above.  
Blastic bone lesions are non-measurable.
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cystic lesions

Lesions that meet the criteria for X-ray defined simple cysts should not be considered as malignant lesions (either measurable or non-measurable) since they are, by definition, simple cysts.  
'Cystic lesions' thought to be cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions are present in the same patient, it is best to consider them as target lesions.
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lesions with prior local treatment

Tumour lesions situated in a previously irradiated area, or in an area subjected to other local therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion.
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2. specifications by methods of

All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should be performed as close as possible to the treatment start.
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(2) method of assessment

The same method of assessment and the same technique should be used to characterise each identified and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, documentation by colour photography including a ruler to estimate the size of the lesion is suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be undertaken since it is more objective and may also be reviewed at the end of the study. Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung. CT/MRI: CT is the best currently available and reproducible method to measure lesions selected for response assessment. This appendix has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, laparoscopy: The utilisation of these techniques for objective tumour evaluation is not advised. However, they can be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response or surgical resection is an endpoint. Tumour markers: Tumour markers alone cannot be used to assess objective tumour response. If markers are initially above the upper normal limit, however, they must normalise for a patient to be considered in complete response. Because tumor markers are disease specific, instructions for their measurement should be incorporated into protocols on a disease specific basis. Specific guidelines for CA-125 response (in recurrent ovarian cancer), have been published. In addition, the Gynecologic Cancer Intergroup has developed CA125 progression criteria which are to be integrated with objective tumour assessment for use in first-line trials in ovarian cancer Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if required by protocol (for example, residual lesions in tumour types such as germ cell tumours, where known residual benign tumours can remain). When effusions are known to be a potential ADR (e.g., with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the measurable tumour has met criteria for response or stable disease in order to differentiate between response (or stable disease) and progressive disease.
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ii. tumour response evaluation 1.

To assess objective response or future progression, it is necessary to estimate the overall tumour burden at baseline and use this as a comparator for subsequent measurements. Only patients with measurable disease at baseline should be included in protocols where objective tumour response is the primary endpoint. Measurable disease is defined by the presence of at least one measurable lesion. In studies where the primary endpoint is tumour progression (either time to progression or proportion with progression at a fixed date), the protocol must specify if entry is restricted to those with measurable disease or whether patients having non-measurable disease only are also eligible.
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2. baseline documentation of "target"

When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline (this means in instances where patients have only one or two organ sites involved a maximum of two and four lesions respectively will be recorded). For evidence to support the selection of only five target lesions, see analyses on a large prospective database in the article by Bogaerts et al. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures which may be visible by imaging even if not involved by tumour. As noted in previous Section 3, pathological nodes which are defined as measurable must meet the criterion of a short axis of ≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid tumour. Nodal size is normally reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, saggital or coronal). The smaller of these measures is the short axis. For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered non-target lesions. Nodes that have a short axis <10 mm are considered non-pathological and should not be recorded or followed. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then as noted above, only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterise any objective tumour regression in the measurable dimension of the disease. All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as 'present', 'absent', or in rare cases 'unequivocal progression' (more details to follow). In addition, it is possible to record multiple nontarget lesions involving the same organ as a single item on the case record form (e.g., 'multiple enlarged pelvic lymph nodes' or 'multiple liver metastases').
clinical trial protocol
3. response criteria

This section provides the definitions of the criteria used to determine objective tumour response for target lesions.
clinical trial protocol
(1) evaluation of target lesions

**Complete Response (CR):** Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have reduction in short axis to <10 mm.  
**Partial Response (PR):** At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.  
**Progressive Disease (PD):** At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).  
**Stable Disease (SD):** Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sumdiameters while on study.
clinical trial protocol
(2) special notes on the

Lymph nodes identified as target lesions should always have the actual short axis measurement recorded (measured in the anatomical plane as the baseline examination), even if the nodes regress to below 10mm on study. This means that when lymph nodes are included as target lesions, the 'sum' of lesions may not be zero even if complete response criteria are met, since a normal lymph node is defined as having a short axis of <10 mm. Case report forms or other data collection methods may therefore be designed to have target nodal lesions recorded in a separate section where, in order to qualify for CR, each node must achieve a short axis <10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
clinical trial protocol
target lesions that become too

While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable assigning an exact measure and may report them as being 'too small to measure'. When this occurs, it is important that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore providing this default value will prevent false responses or progressions based upon measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be recorded, even if it
clinical trial protocol
is below 5 mm. lesions

When non-nodal lesions 'fragment', the longest diameters of the fragmented portions should be added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that they are no longer separable, the longest diameter in this instance should be the maximal longest diameter for the 'coalesced lesion'.
clinical trial protocol
(3) evaluation of non-target lesions

This section provides the definitions of the criteria used to determine the tumour response for the group of non-target lesions. While some non-target lesions may actually be measurable, they need not be measured and instead should be assessed only qualitatively at the time points specified in the protocol.  
CR: Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).  
**Non-CR/Non-PD:** Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.  
**Progressive Disease (PD):** Unequivocal progression (see comments below) of existing nontarget lesions. (Note: the appearance of one or more new lesions is also considered progression).
clinical trial protocol
(4) special notes on assessment

The concept of progression of non-target disease requires additional explanation as follows: When the patient also has measurable disease. In this setting, to achieve 'unequivocal progression' on the basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumour burden has increased sufficiently to merit discontinuation of therapy. A modest 'increase' in the size of one or more non-target lesions is usually not sufficient to quality for unequivocal progression status. The designation of overall progression solely on the basis of change in nontarget disease in the face of SD or PR of target disease will therefore be extremely rare. When the patient has only non-measurable disease. This circumstance arises in some phase III trials when it is not a criterion of study entry to have measurable disease. The same general concepts apply here as noted above, however, in this instance there is no measurable disease assessment to factor into the interpretation of an increase in non-measurable disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for unequivocal progression is to consider if the increase in overall disease burden based on the change in nonmeasurable disease is comparable in magnitude to the increase that would be required to declare PD for measurable disease: i.e.an increase in tumour burden representing an additional 73%
increase in 'volume' (which is equivalent to a 20% increase diameter in a measurable lesion). Examples include an increase in a pleural effusion from 'trace' to 'large', an increase in lymphangitic disease from localised to widespread, or may be described in protocols as 'sufficient to require a change in therapy'. If 'unequivocal progression' is seen, the patient should be considered to have had overall PD at that point. While it would be ideal to have objective criteria to apply to non-measurable disease, the very nature of that disease makes it impossible to do so, therefore the increase must be substantial.
clinical trial protocol
(5) new lesions

The appearance of new malignant lesions denotes disease progression; therefore, some comments on detection of new lesions are important. There are no specific criteria for the identification of new radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning technique, change in imaging modality or findings thought to represent something other than tumour (for example, some 'new' bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important when important when the patient's baseline lesions show complete response. For example, necrosis of a liver lesion may be reported on a CT scan report as a "new" cystic lesion, which it is not. A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression. An example of this is the patient who has visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. The patient's brain metastases are considered to be evidence of PD even if he/she did not have brain imaging at baseline. If a new lesion is equivocal, for example because of its small size, continued therapy and followup evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then progression should be declared using the date of the initial scan. While FDG-PET assessments need additional study, it is reasonable to incorporate the use of FDG- PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow- up:
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.
clinical trial protocol
4. evaluation of best overall

The best overall response is the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. On occasion a response may not be documented until after the end of therapy so protocols should be clear if post-treatment assessments are to be considered in determination of best overall response. Protocols must specify how any new therapy introduced before progression will affect best response designation. The patient's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may also require confirmatory measurement. Specifically, in non-randomised trials where response is the primary endpoint, confirmation of PR or CR is needed to deem either one the 'best overall response'. This is described further below.
clinical trial protocol
(1) time point response

It is assumed that at each protocol specified time point, a response assessment occurs. Table 4 provides a summary of the overall response status calculation at each time point for patients who have measurable disease at baseline. When patients have non-measurable (non-target) disease only, Table 5 is to be used.  
| Target lesions   | Non-target lesions      | New lesions   | Overall response   |
|------------------|-------------------------|---------------|--------------------|
| CR               | CR                      | No            | CR                 |
| CR               | Non-CR/non-PD           | No            | PR                 |
| CR               | Not evaluated           | No            | PR                 |
| PR               | Non-PD or not evaluated | No            | PR                 |
| SD               | Non-PD or not evaluated | No            | PD                 |
| Not evaluated    | Non-PD                  | No            | Non-evaluable      |  
| Target lesions                                                                    | Non-target lesions   | New lesions   | Overall response   |
|-----------------------------------------------------------------------------------|----------------------|---------------|--------------------|
| PD                                                                                | Any                  | Yes or No     | PD                 |
| Any                                                                               | PD                   | Yes or No     | PD                 |
| Any                                                                               | Any                  | Yes           | PD                 |
| Abbreviation: CR = complete response; PR = partial response; SD = stable disease. |                      |               |                    |  
| Table 5 Time point response: patients with non-target disease only   |             |                  |
|----------------------------------------------------------------------|-------------|------------------|
| Non-target lesions                                                   | New lesions | Overall response |
| CR                                                                   | No          | CR               |
| Non-CR/non-PD                                                        | No          | Non-CR/non-PDa   |
| Not evaluated                                                        | No          | Non-evaluable    |
| Definite disease progression                                         | Yes or No   | PD               |
| Any                                                                  | Yes         | PD               |
| Abbreviation: CR = complete response; SD = stable disease.           |             |                  |  
Note: 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly used as endpoint for assessment in some trials so to assign this category when no lesions can be measured is not advised.
clinical trial protocol
(2) missing assessments and inevaluable

When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at that time point. If only a subset of lesion measurements are made at an assessment, usually the case is also considered NE at that time point, unless a convincing argument can be made that the contribution of the individual missing lesion(s) would not change the assigned time point response. This would be most likely to happen in the case of SD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution of the missing lesion.
clinical trial protocol
(3) best overall response all

The best overall response is determined once all the data for the patient is known. Best response determination in trials where confirmation of complete or partial response IS NOT required: Best response in these trials is defined as the best response across all time points (for example, a patient who has SD at first assessment, PR at second assessment, and PD on last assessment has a best overall response of PR). When SD is believed to be best response, it must also meet the protocol specified minimum time from baseline. If the minimum time is not met when SD is otherwise the best time point response, the patient's best response depends on the subsequent assessments. For example, a patient who has SD at first assessment, PD at second and does not meet minimum duration for SD, will have a best response of PD. The same patient lost to follow-up after the first SD assessment would be considered inevaluable. Best response determination in trials where confirmation of complete or partial response IS required: Complete or partial responses may be claimed only if the criteria for each are met at a subsequent time point as specified in the protocol. In this circumstance, the best overall response can be interpreted as in Table 6.  
| Table 6 Best overall response when confirmation of CR and PR required                                                                                                                               |                                          |                                                                 |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------|-----------------------------------------------------------------|
| Overall  response First time point                                                                                                                                                                  | Overall  response Subsequent  time point | BEST overall response                                           |
| CR                                                                                                                                                                                                  | CR                                       | CR                                                              |
| CR                                                                                                                                                                                                  | PR                                       | SD, PD or PRa                                                   |
| CR                                                                                                                                                                                                  | SD                                       | SD provided minimum criteria for SD duration met, otherwise, PD |
| CR                                                                                                                                                                                                  | PD                                       | SD provided minimum criteria for SD duration met, otherwise, PD |
| CR                                                                                                                                                                                                  | Non-evaluable                            | SD provided minimum criteria for SD duration met, otherwise, NE |
| PR                                                                                                                                                                                                  | CR                                       | PR                                                              |
| PR                                                                                                                                                                                                  | PR                                       | PR                                                              |
| PR                                                                                                                                                                                                  | SD                                       | SD                                                              |
| PR                                                                                                                                                                                                  | PD                                       | SD provided minimum criteria for SD duration met, otherwise, PD |
| PR                                                                                                                                                                                                  | Non-evaluable                            | SD provided minimum criteria for SD duration met, otherwise, NE |
| Non-evaluable                                                                                                                                                                                       | Non-evaluable                            | Non-evaluable                                                   |
| Abbreviation: CR = complete response; PR = partial response; SD = stable disease. Note: a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease |                                          |                                                                 |  
Note: a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether minimum duration for SD was met. However, sometimes
'CR' may be claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
clinical trial protocol
(4) special notes on response

When nodal disease is included in the sum of target lesions and the nodes decrease to 'normal' size (<10 mm), they may still have a measurement reported on scans. This measurement should be recorded even though the nodes are normal in order not to overstate progression should it be based on increase in size of the nodes. As noted earlier, this means that patients with CR may not have a total sum of 'zero' on the case report form (CRF). In trials where confirmation of efficacy is required, repeated 'NE' time point assessments may complicate best response determination. The analysis plan for the trial must address how missing data/assessments will be addressed in determination of response and progression. For example, in most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a confirmed response. Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as 'symptomatic deterioration'. Every effort should be made to document objective progression even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective response, and it is a reason for stopping study therapy. The objective response status of such patients is to be determined by evaluation of target and non-target disease as shown in Tables 4-6. Conditions that define 'early progression, early death and inevaluability' are study specific and should be clearly described in each protocol (depending on treatment duration, treatment periodicity). In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response depends upon this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of progression should be the earlier date when progression was suspected.
clinical trial protocol
5. frequency of tumour re-evaluation

Frequency of tumour re-evaluation while on treatment should be protocol specific and adapted to the type and schedule of treatment. However, in the context of phase II studies where the beneficial effect of therapy is not known, follow-up every 6-8 weeks is reasonable. Smaller or greater time intervals than these could be justified in specific regimens or circumstances. The protocol should specify which organ sites are to be evaluated at baseline (usually those most likely to be involved with metastatic disease for the tumour type under study) and how often evaluations are repeated. Normally, all target and non-target sites are evaluated at each assessment. In selected circumstances certain non-target organs may be evaluated less frequently. For example, bone scans may need to be repeated only when complete response is identified in target disease or when progression in bone is suspected. After the end of the treatment, the need for repetitive tumour evaluations depends on whether the trial has as a goal the response rate or the time to an event (progression/death). If 'time to an event' (e.g., time to progression, disease-free survival, progression-free survival) is the main endpoint of the study, then routine re-evaluation of protocol specified sites of disease is warranted. In randomised comparative trials in particular, the scheduled assessments should be performed as identified on a calendar schedule (for example: every 6-8 weeks on treatment or every 3-4 months after treatment) and should not be affected by delays in therapy, drug holidays or any other events that might lead to imbalance in a treatment arm in the timing of disease assessment.
clinical trial protocol
6. confirmatory measurement/duration of response

In non-randomised trials where response is the primary endpoint, confirmation of PR and CR is required to ensure responses identified are not the result of measurement error. This will also permit appropriate interpretation of results in the context of historical data where response has traditionally required confirmation in such trials (see the paper by Bogaerts et al. in this Special Issue). However, in all other circumstances i.e. in randomised trials (phase II or III) or studies where stable disease or disease progression are the primary endpoints, confirmation of response is not required since it will not add value to the interpretation of trial results. However, elimination of the requirement for response confirmation may increase the importance of central review to protect against bias, in particular in studies which are not blinded. In the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval (in general not less than 6-8 weeks) that is defined in the study protocol.
clinical trial protocol
(2) duration of overall response

The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements
clinical trial protocol
recorded on study).

The duration of overall complete response is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.
clinical trial protocol
(3) duration of stable disease

Stable disease is measured from the start of the treatment (in randomised trials, from date of randomisation) until the criteria for progression are met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the reference for calculation of PD). The clinical relevance of the duration of stable disease varies in different studies and diseases. If the proportion of patients achieving stable disease for a minimum period of time is an endpoint of importance in a particular trial, the protocol should specify the minimal time interval required between two measurements for determination of stable disease. Note: The duration of response and stable disease as well as the progression-free survival are influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of RECIST to define a standard follow-up frequency. The frequency should take into account many parameters including disease types and stages, treatment periodicity and standard practice. However, these limitations of the precision of the measured endpoint should be taken into account if comparisons between trials are to be made.
clinical trial protocol
7. progression-free survival/proportion progression-free (1)

This RECIST guideline is focused primarily on the use of objective response endpoints for phase II trials. In some circumstances, 'response rate' may not be the optimal method to assess the potential anticancer activity of new agents/regimens. In such cases 'progression-free survival' (PFS) or the 'proportion progression-free' at landmark time points, might be considered appropriate alternatives to provide an initial signal of biologic effect of new agents. It is clear, however, that in an uncontrolled trial, these measures are subject to criticism since an apparently promising observation may be related to biological factors such as patient selection and presence/absence of the impact of the intervention. Thus, phase II trials utilising these endpoints are best designed with a randomised control. Exceptions may exist where the behaviour patterns of certain cancers are so consistent (and usually consistently poor), that a non-randomised trial is justifiable (see for example van Glabbeke et al.). However, in these cases it will be essential to document with care the basis for estimating the expected PFS or proportion progression-free in the absence of a treatment effect.
clinical trial protocol
8. independent review of response

For trials where objective response (CR + PR) is the primary endpoint, and in particular where key drug development decisions are based on the observation of a minimum number of responders, it is recommended that all claimed responses be reviewed by an expert(s) independent of the study. If the study is a randomised trial, ideally reviewers should be blinded to treatment assignment.  
Simultaneous review of the patients' files and radiological images is the best approach.  
Independent review of progression presents some more complex issues: for example, there are statistical problems with the use of central-review-based progression time in place of investigatorbased progression time due to the potential introduction of informative censoring when the former precedes the latter. An overview of these factors and other lessons learned from independent review is provided in an article by Ford et al. in this special issue.
clinical trial protocol
9. reporting best response results

When response is the primary endpoint, and thus all patients must have measurable disease to enter the trial, all patients included in the study must be accounted for in the report of the results, even if there are major protocol treatment deviations or if they are not evaluable. Each patient will be assigned one of the following categories:
1. CR 2. PR 3. SD  
4. PD
5. Inevaluable for response: specify reasons [for example: early death, disease; early death, toxicity; tumour assessments not repeated/incomplete; other (specify)]. Normally, all eligible patients should be included in the denominator for the calculation of the response rate for phase II trials (in some protocols it will be appropriate to include all treated patients). It is generally preferred that 95% two-sided confidence limits are given for the calculated response rate. Trial conclusions should be based on the response rate for all eligible (or all treated) patients and should not be based on a selected 'evaluable' subset.
clinical trial protocol
appendix ii ecog performance status

| Appendix II: ECOG Performance Status Score Scale Grade Description 0 Fully active, able to carry on all pre-disease performance without restriction. 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light house work, office work). 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about  more than 50% of waking hours. 3 Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 5 Dead   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Appendix III: Definition of Women of Childbearing Potential and Contraceptive
clinical trial protocol
requirements - definition of women

Women of non-child-bearing potential are defined as postmenopausal women and premenopausal women who have undergone sterilization. Sterilization includes bilateral tubal ligation or bilateral oophorectomy or hysterectomy.  
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, antiMullerian hormone can be tested additionally. This test will be performed at screening only.  
3) For women ≥60 years of age, a pregnancy-related test is not required.  
Women of childbearing age are defined as women who have not undergone sterilization and are able to become pregnant anatomically and physiologically after menarche and before menopause.
clinical trial protocol
- contraceptive requirements

For women of childbearing potential, the results of serum pregnancy should be negative at screening and baseline (if applicable). Males of reproductive potential and females of childbearing potential must also agree to one of the following from the time of signing the ICF through the last dose of study drug:
Total abstinence. Periodic abstinence methods (such as calendar method, ovulation method, symptom-body temperature method, post-ovulation method) are not allowed.  
One of the contraceptive methods with a failure rate of <1%:
- Intrauterine device or intrauterine hormone release system with an annual failure rate of
<1%;
- Males undergo vasoligation; - Double barrier method: Condoms and/or occlusion caps (diaphragm or cervical cap/dome cap), spermicide (foam/gel/film/cream/suppository) barrier method should be used as supplementary measures Within 6 months after the last administration, you can also accept the following contraceptive methods:
Reasonable combined use of oral/injection/transdermal hormonal contraceptives that can inhibit ovulation (including estrogen and progesterone);
Reasonable use of progesterone-only oral/injection/transdermal hormonal contraceptives that can inhibit ovulation.  
| Appendix IV: Examples of CYP450 Related Drugs/Foods Categories Examples of related drugs/foods Strong CYP3A4 inhibitors Clarithromycin Telithromycin Itraconazole Ketoconazole Voriconazole Posaconazole Lopinavir Indinavir Nelfinavir Ritonavir Saquinavir Conivaptan Mibefradil Nefazodone Troleandomycin Grapefruit, pomelos and other citrus fruits or juice Strong CYP3A4 inducers Carbamazepine Efavirenz Modafinil Nevirapine Phenobarbital Phenytoin Rifampin St John's Wort Strong CYP3A5 inhibitors Clarithromycin Telithromycin Itraconazole Ketoconazole Voriconazole Posaconazole Lopinavir Indinavir Nelfinavir Ritonavir Saquinavir Conivaptan Mibefradil Nefazodone   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Troleandomycin Grapefruit, pomelos and other citrus fruits or juice                                                |                                                                                                  |
|--------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|
| Strong CYP3A5 inducers                                                                                             | Carbamazepine Efavirenz Modafinil Nevirapine Phenobarbital Phenytoin Rifampin St John's Wort     |
| Sensitive CYP3A4 substrates  with a narrow therapeutic  index                                                      | Alfentanil Cyclosporine Diergotamine Ergotamine Fentanyl Pimozide Quinidine Sirolimus Tacrolimus |
| Sensitive CYP2B6 substrates  with a narrow therapeutic  index                                                      | Bupropion, efavirenz                                                                             |
| Note: For the drugs listed and not listed in the above list, if the investigator cannot determine whether they are |                                                                                                  |  
Note: For the drugs listed and not listed in the above list, if the investigator cannot determine whether they are strong CYP3A4 inhibitors, strong CYP3A4 inducers, strong CYP3A5 inhibitors, strong CYP3A5 inducers, sensitive CYP3A4 substrates with a narrow therapeutic index, or sensitive CYP2B6 substrates with a narrow therapeutic index, the sponsor can be contacted for discussion and decision.
clinical trial protocol
list of references

[1] FDA guidance drug interaction studies: study design, data analysis, and implication for dosing and labeling, 2006.  
[2] Oncology Clinical Pharmacology internal memo: drug-drug Interactions (DDI) database, 2010.  
[3] Zhou SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008;9(4):310-322.  
[4] https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-tablesubstrates-inhibitors-and-inducers\#table2-2
[5] http://medicine.iupui.edu/clinpharm/ddis/clinical-table/  
| Appendix V: Transporter Inhibitors and Substrates Examples Categories Examples of related drugs/foods BCRP substrates sulfasalazine (Narrow therapeutic index at the discretion of  the investigator) rosuvastatin P-gp substrates dabigatran etexilate (Narrow therapeutic index at the discretion of  the investigator) fexofenadine digoxin OAT1 substrates adefovir (Narrow therapeutic index at the discretion of  the investigator) cefaclor ceftizoxime furosemide ganciclovir famotidine methotrexate oseltamivir carboxylate OAT3 substrates adefovir (Narrow therapeutic index at the discretion of  the investigator) cefaclor ceftizoxime furosemide ganciclovir famotidine methotrexate oseltamivir carboxylate OATP1B3 substrates pravastatin (Narrow therapeutic index at the discretion of  the investigator) repaglinide atorvastatin bosentan asunaprevir danoprevir rosuvastatin docetaxel fexofenadine glyburide nateglinide paclitaxel pitavsatatin simvastatin acid MATE1 substrates Metformin(Narrow therapeutic index at the discretion of   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Categories                                                                                                         | Examples of related drugs/foods                                                            |
|--------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|
| the investigator) MATE2-K substrates                                                                               | Metformin                                                                                  |
| (Narrow therapeutic index at the discretion of  the investigator) BCRP inhibitors                                  | curcumin                                                                                   |
| (Strong inhibitor at the discretion of the  investigator)                                                          | eltrombopag cyclosporine A                                                                 |
| P-gp inhibitors                                                                                                    | ranolazine                                                                                 |
| (Strong inhibitor at the discretion of the  investigator)                                                          | verapamil itraconazole clarithromycin quinidine ritonavir elaprevir saquinavir + ritonavir |
| Note: For the drugs listed and not listed in the above list, if the investigator cannot determine whether they are |                                                                                            |  
Note: For the drugs listed and not listed in the above list, if the investigator cannot determine whether they are BCRP substrates, P-gp substrates, OAT1 substrates, OAT3 substrates, OATP1B3 substrates, MATE1 substrates, MATE2-K substrates, strong BCRP inhibitors, or strong P-gp inhibitors with a narrow therapeutic index, the sponsor can be contacted for discussion and decision.  
[1] https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substr ates-inhibitors-and-inducers\#table2-2
[2] CDE Technical Guidelines for Drug Interaction Research (Trial)  
| Appendix VI: Drugs which May Prolong QT Interval and (or) Induce Torsade De Pointes Categories Common drugs ANTIARRHYTHMIC  Amiodarone (Cordarone ®) (Pacerone ®) AGENTS Disopyramide (Norpace ®) Dofetilide (Tikosyn ®) Ibutilide (Corvert ®) Procainamide (Pronestyl ®) (Procan ®) Quinidine (Quinaglute ®) (Cardioquin ®) Sotalol (Betapace ®) ANTIBIOTICS Clarithromycin (Biaxin ®) Erythromycin (Erythrocin ®) (E.E.S. ®) Gatifloxacin Moxifloxacin Sparfloxacin (Zagam ®) ANTIPSYCHOTICS Chlorpromazine (Thorazine ®) Haloperidol (Haldol ®) Mesoridazine (Serentil ®) Pimozide (ORAPI ®) Risperidone Thioridazine (Mellaril ®) Ziprasidone ANTIDEPRESSANTS Amitriptyline Desipramine Doxepin Imipramine Maprotiline Venlafaxine ANTIFUNGALS Ketoconazole Itraconazole ANTIMALARIALS Chloroquine (Arelan ®) Halofantrine (Halfan ®) ANTIEMETICS Dolasetron Domperidone (Motillium ®) Droperidol (Inapsine ®) Ondansetron Tropisetron Others Arsenic trioxide (Trisenox ®) Bepridil (Vascor ®) Methadone (Methadose ®) Pentamidine (NebuPent ®) Cisapride (Propulsid ®) Tacrolimus   |
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