clinical trial protocol
1.5.1 pharmacology primary pharmacodynamics

The study of compounds effects **on FGFR4 kinase** detected the inhibitory activity of BLU-554 and BB102 on FGFR4, and the half maximal inhibitory concentration (IC50) of BLU-554 and BB102 were 13.94 nM and 2.522 nM, respectively, showing strong inhibitory effects. Compared with BLU-554, BB102 has higher inhibitory activity on FGFR4. The study of **inhibitory effect** of BB102 on the FGF19/FGFR4-mediated signal pathway in human hepatocellular carcinoma Hep 3B cells showed that BB102 completely inhibited ERK and AKT protein phosphorylation which is downstream of FGF19/FGFR4 in human hepatocellular carcinoma cell Hep 3B even at 16.7 nM, and its inhibitory potency was similar to FGF401 and stronger than BLU-
554. It was demonstrated that BB102 inhibited the growth of hepatocellular carcinoma Hep 3B
cells by selectively inhibiting the kinase activity of FGFR4, thereby inhibiting its downstream ERK/AKT signal pathway. The study of inhibitory activity on **cell proliferation** showed that BB102 had a strong inhibitory effect on the proliferation of FGF19/FGFR4 high-expressing tumor cells, such as human hepatocellular carcinoma cells Hep 3B, HuH-7 and JHH-7, human breast cancer cell MDA-MB- 453, and human rhabdomyosarcoma cell SJCRH30. The inhibitory effect of BB102 on Hep 3B,
HuH-7 and JHH-7 was IC50 = 5.8 nM, 8.7 nM and 21.760 nM, respectively, which was better than the positive control BLU-554 (IC50 = 23.7 nM, 30.7 nM and 87.980 nM), and slightly worse than the positive control FGF401 (IC50 = 2.3 nM, 3.2 nM and 10.810 nM). The IC50 of BB102 on SJCRH30 was 1.9 nM, which was better than that of positive control BLU-554 (IC50 = 5.2 nM) and slightly worse than that of positive control FGF401 (IC50 = 0.6 nM). The IC50 of BB102 on MDA-MB-453 was 24.7 nM, which was slightly worse than that of positive control FGF401 and BLU-554 (IC50 = 9.5 nM and 6.6 nM). **In addition,** BB102 also had a strong inhibitory effect on the proliferation of Ba/F3 cell lines with FGFR4V550L or FGFR4N535K mutation (IC50 = 0.045 μM
and 0.023 μM, respectively), which was better than the positive control BLU-554 (IC50 = 0.572 μM and 0.206 μM, respectively). In the *in vivo* **pharmacodynamic study,** five FGF19/FGFR4 high-expressing xenograft models were selected: human hepatocellular carcinoma cells Hep 3B, HuH-7 and JHH-7, human breast cancer cell MDA-MB-453, and human rhabdomyosarcoma cell SJCRH30. The study of "Inhibitory Effect of BB102 on the Growth of Subcutaneous Xenografts of Human Hepatocellular Carcinoma HuH-7 cells in Balb/c nude Mice" consisted of 7 groups, including the vehicle control group (BID, 21 days), the positive control sorafenib 60 mg/kg group (QD, 21 days), the positive control BLU-554 30 mg/kg group (BID, 21 days), positive control BB181 (FGF401 citrate) 30 mg/kg group (BID, 21 days), BB102-citrate 30 mg/kg group (BID, 21 days), BB102-citrate 60 mg/kg group ( BID, 21 days), BB102-citrate 90 mg/kg group (BID, 7 days; QD, 14 days). On Day 20 after treatment, compared with the vehicle control group, BB102-citrate had a significant antitumor effect at doses of 30 mg/kg, 60 mg/kg and 90 mg/kg, with the treatment/control ratio (T/C) value of 19.35%, 14.52% and 13.55%, respectively; tumor growth inhibition (TGI) values of 96.21%, 101.97% and 103.12%, respectively. The positive control FGF401 at 30 mg/kg had significant antitumor effect compared with the vehicle control group, with the T/C value of 15.31% and TGI value of 101.04%, measured on Day 20 after treatment; Sorafenib at 60 mg/kg had moderate antitumor effect with the T/C value of 32.75% and TGI value of 80.10%, measured on Day 20 after treatment. BLU-554 at 30 mg/kg had slight antitumor effect with the T/C value of 68.59% and TGI value of 37.49%, measured on Day 20 after treatment. The antitumor effect of BB102 in this model was similar to that of positive control FGF401, and was significantly better than that of positive control sorafenib and BLU-554. The study 1 of
"Inhibitory Effect of BB102 on the Growth of Subcutaneous Xenografts of Human Hepatocellular Carcinoma JHH-7 cells in Balb/c nude Mice" consisted of 5 groups, including the vehicle control group, positive control BB181 (FGF401-citrate) 10 mg/kg group, BB102citrate 10 mg/kg group, BB102-citrate 30 mg/kg group, and BB102-citrate 60 mg/kg group; BID, administered orally for 18 days. Compared with the vehicle control group, BB102-citrate had no significant antitumor effect at dose of 10 mg/kg; BB102-citrate had a certain antitumor effect at dose of 30 mg/kg; BB102-citrate showed significant antitumor effect at dose of 60 mg/kg. The T/C value on Day 17 of these 3 dosing groups was 94.07%, 69.75% and 46.51%, respectively; TGI value was 6.17%, 31.51% and 55.69%, respectively. Compared with the vehicle control group, positive control FGF401-citrate at 10 mg/kg had no significant antitumor effect with the T/C value of 86.61% and TGI value of 13.95% on Day 17 after treatment. **The study 2** consisted of 4 groups, including the vehicle control group, positive control BLU-554 60 mg/kg group, BB102-citrate 60 mg/kg group, and BB102-citrate 80 mg/kg group; BID, administered orally for 3 weeks. Compared with the vehicle control group, BB102-citrate had a significant antitumor effect at doses of 60 mg/kg and 80 mg/kg, with T/C value of 36.07% and 20.04%, respectively, measured on Day 20 after treatment; TGI value was 66.44% and 83.10%, respectively. Compared with the vehicle control group, the positive control BLU-554 had a significant antitumor effect at a dose of 60 mg/kg with the T/C value of 43.22% and TGI value of 59.02%, measured on Day 20 after treatment. Considering the results of the two studys, BB102-citrate significantly inhibited the growth of human hepatocellular carcinoma JHH-7 cell mouse xenografts with dose dependent manner, the high dose group had the best antitumor effect, and the effect decreased along with the decrease of dose. The antitumor effect of BB102 in this model was slightly better than that of positive control BLU-554. The study of "Inhibitory Effect of BB102 on the Growth of Subcutaneous Xenografts of Human Breast Cancer MDA-MB-453 cells in B-NDG Mice" consisted of 3 groups, including the vehicle control group (BID, 22 days), BB102-citrate 80 mg/kg group (BID, 22 days), and positive control BLU-554 80 mg/kg group (BID, 22 days). The results showed that BB102-citrate 80 mg/kg had a significant antitumor effect compared with the vehicle control group with the T/C value of 28.01% and TGI value of 120.94%, measured on Day 21 after treatment. The positive control BLU-554 80 mg/kg had a significant antitumor effect compared with the vehicle control group with the T/C value of 23.01% and TGI value of 129.35%, measured on Day 21 after treatment. The antitumor effect of BB102 in this model was similar to that of positive control BLU-554. **The study of "Inhibitory Effect of BB102 on the Growth of Subcutaneous** Xenografts of Human Rhabdomyosarcoma SJCRH30 cells in Balb/c nude Mice" consisted of 3 groups, including the vehicle control group (BID, 22 days), BB102-citrate 60 mg/kg group (BID, 22 days), and positive control BLU-554 60 mg/kg group (BID, 22 days). The results showed that BB102-citrate had a significant antitumor effect at a dose of 60 mg/kg compared with the vehicle control group, with T/C value of 28.97% and TGI value of 76.10%, measured on day 21 after treatment. The positive control BLU-554 had a significant antitumor effect at a dose of 60 mg/kg compared with the vehicle control group, with T/C value of 28.65% and TGI value of 77.11%, measured on day 21 after treatment. The antitumor effect of BB102 in this model was similar to that of positive control BLU-554. The study of "Inhibitory Effect of BB102 on the Growth of Subcutaneous Xenograft Tumor of Human Hepatocellular Carcinoma Hep 3B cells in CB17.SCID Mice" consisted of 5 groups, including the vehicle control group, positive control BB181 (FGF401-citrate) 5 mg/kg group, BB102-citrate 5 mg/kg group, BB102-citrate 10 mg/kg group, and BB102-citrate 30 mg/kg group; BID, administered orally for 3 weeks. The results showed that BB102-citrate had a significant antitumor effect compared with the vehicle control group at doses of 5 mg/kg, 10 mg/kg and 30 mg/kg, with T/C values of 54.19%, 43.26% and 8.36%, respectively; TGI values of 48.51%, 60.09% and 97.04%, respectively. Positive control FGF401citrate at 5 mg/kg had a significant antitumor effect compared with the vehicle control group with the T/C value of 38.52% and TGI value of 65.11%, measured on Day 20 after treatment. The BB102-citrate significantly inhibited the growth of human hepatocellular carcinoma Hep 3B cell mouse xenografts in a dose-dependent manner: the high-dose group had the best effect, and the effect decreased with the decrease of dose. The antitumor effect of BB102 in this model was similar to that of positive control FGF401.
clinical trial protocol
secondary pharmacodynamics

In the *in vitro* **kinase selectivity study**, for 207 kinases (such as FGFR4, HCK, PAK3, NEK2, MET, PIM3, FGFR1, ZAP70, AurA, etc.), 1 μM BB102 had an inhibitory effect on FGFR4 only and the inhibition rate was up to 102.03%. However, BB102 had no inhibitory effect on the other kinases (%Inh <40%). The above results showed that BB102 has extremely high kinase selectivity, and its inhibitory activity on FGFR4 kinase is more than 400 times higher than that of other 206 kinases. The inhibitory effect of BB102 on the proliferation of tumor cells with different expression levels of FGF19/FGFR4 was evaluated by the cell proliferation inhibition experiment. The results showed that BB102 showed a strong inhibitory effect on the proliferation of FGF19/FGFR4 highexpressing tumor cells, such as human hepatocellular carcinoma cells Hep 3B and HuH-7, human breast cancer cell MDA-MB-453, and human rhabdomyosarcoma cell SJCRH30 (IC50 was 5.8, 8.7, 24.7 and 1.9 nM, respectively). However, BB102 showed little or no inhibitory effect on FGF19/FGFR4 low-expressing tumor cells such as human hepatocellular carcinoma cells SNU- 387 and SNU-878, human rhabdomyosarcoma cell RD and human colon adenocarcinoma cell HT-
29 (IC50 of RD cell >10 μM, and IC50 of other cells >20 μM).  
Meanwhile, BB102 had no inhibitory effect on the proliferation of normal cells, such as mouse embryonic fibroblast NIH3T3, human umbilical vein vessel endothelial cell HUVEC, and human normal lung epithelial cell BEAS-2B (IC50 >20 μM).
clinical trial protocol
safety pharmacology

The results of the safety pharmacology showed that BB102 was expected to have no adverse effects on the cardiovascular system, respiratory system, or central nervous system in humans. The IC50 of BB102 inhibiting the hERG current was >12 µM (maximum solubility of BB102 under test conditions) in the human embryonic kidney cell lines (hERG-HEK293) with stable expression of hERG channels. A single oral administration of BB102-citrate in Beagle dogs at doses of 40, 100 and 250 mg/kg had no significant test article-related changes in any of the evaluated cardiovascular parameters including blood pressure (systolic blood pressure, diastolic blood pressure, mean arterial blood pressure), heart rate, ECG (RR interval, PR interval, QRS duration, QT and corrected QT intervals) and body temperature. Single oral dosing with BB102-citrate up to 300 mg/kg in SD rats had no test article-related notable effects on respiratory parameters, including tidal volume, minute volume and respiratory rate. Single oral dosing of BB102-citrate to SD rats up to 300 mg/kg had no effect on the evaluated neurobehavioral parameters.
clinical trial protocol
1.5.2 (nonclinical) pk absorption

Caco-2 cells permeability study: BB102-citrate was a moderate permeability compound, and it is a substrate of efflux transporters. Single-dose and 7-day repeat-dose PK studies in SD **rats**: Following intravenous (2 mg/kg) and oral administration at 3 dose levels (30 mg/kg, 90 mg/kg and 270 mg/kg) of BB102-citrate in SD
rats, there was no significant gender differences in drug exposure (AUClast) of BB102 in both intravenous group (the male/female ratio was 0.663) and single-dose oral groups (the male/female ratios were 0.537-0.750), while the exposure (AUClast) in males was slightly lower than that in females in repeat-dose oral groups (the male/female ratios were 0.437-0.647). Following intravenous administration of BB102-citrate at 2 mg/kg in SD rats, the AUClast of BB102 in males and females was 2194 h*ng/mL and 3308 h*ng/mL, respectively; BB102 was a low clearance compound in SD rats, and it was widely distributed in rat body. Following single oral administration of BB102-citrate at three dose levels (i.e., 30 mg/kg, 90 mg/kg and 270 mg/kg) in SD rats, in males, the AUClast were 27209 h*ng/mL, 50642 h*ng/mL and 160093 h*ng/mL, respectively; the Cmax were 5927 ng/mL, 8460 ng/mL and 10253 ng/mL, respectively; the half-life
(T1/2) were 5.18 h, 4.51 h and 6.00 h, respectively; in females, the AUClast were 36269 h*ng/mL,
92869 h*ng/mL and 297985 h*ng/mL, respectively; the Cmax were 8733 ng/mL, 12067 ng/mL and 15700 ng/mL, respectively; the T1/2 were 6.47 h, 6.80 h and 5.13 h, respectively. In the dose range of 30-270 mg/kg, in both female and male rats, the increase of Cmax was lower than doseproportional, while the increase of AUClast was close to dose-proportional. Following 7-day repeat oral administration of BB102-citrate at 90 mg/kg in SD rats, in males and females, the Cmax ratios between Day 7 and Day 1 were 0.905 and 1.23, respectively; the AUClast ratios were 0.858 and 1.27, respectively, indicating that there was no obvious drug accumulation of BB102 in rats. When it was calculated using AUClast, following single oral administration of BB102-citrate at 30 mg/kg in SD rats, the absolute bioavailability of BB102 in males and females were 82.7% and 73.1%,
respectively. Following oral administration of BB102-citrate at 90 mg/kg in SD rats at fasted and fed conditions, in males and females, the Cmax ratios between fasted and fed group were 1.11 and 0.919, respectively; the AUClast ratios were 1.21 and 1.02, respectively, indicating that food had no significant effect on BB102 exposure in rats. Single-dose and 7-day repeat-dose **PK studies in Beagle Dogs**: Following intravenous and oral administration of BB102-citrate in Beagle dog, the AUClast ratio between males and females was 1.00-1.34, and the Cmax ratio between males and females was 0.983-1.38, indicating that there was no obvious gender difference for the exposure. Following intravenous administration of BB102citrate at 1 mg/kg in Beagle dogs, the AUClast of BB102 in Beagle dogs was 2040 h*ng/mL; BB102 was a low clearance compound in Beagle dog, and it was extensively distributed in Beagle dogs. Following single oral administration of BB102-citrate at three dose levels (i.e., 10 mg/kg, 30 mg/kg and 90 mg/kg) in Beagle dog, the AUClast were 14562 h*ng/mL, 27598 h*ng/mL and 27415 h*ng/mL, respectively; the Cmax were 4492 ng/mL, 8687 ng/mL and 8292 ng/mL, respectively; the T1/2 were 6.54 h,6.30 h and 7.26 h, respectively. The increase of Cmax and AUClast were slightly lower than dose-proportional in the dose range of 10-30 mg/kg; however, Cmax and AUClast did not increase in the dose range of 30-90 mg/kg. It was speculated that there might be saturated absorption in the animals (Beagle dogs) in the dose range of 30-90 mg/kg. Following 7-day repeat oral administration of BB102-citrate at 30 mg/kg, the Cmax and AUClast ratios between Day 7 and Day 1 in Beagle dog were 1.07 and 1.22, respectively, indicating there was no obvious accumulation of BB102 in Beagle dog following 7-day repeat-dose at 30 mg/kg. When it was calculated using AUClast, following single oral administration of BB102-citrate at 10 mg/kg in Beagle dog, the absolute bioavailability in Beagle dog was 71.1%.
clinical trial protocol
distribution

Plasma protein binding: The plasma protein binding of BB102-citrate was not concentration dependent over the range of 0.5-50 μM in the dog, monkey, or human plasma. The mean bound fraction was 0.704, 0.748 and 0.834, respectively. In the mouse and rat plasma, there was a trend for higher unbound fraction at higher BB102-citrate concentrations over the range of 0.5-50 μM. At the test concentrations of 0.5, 5 and 50 μM, the bound fraction was 0.880, 0.881 and 0.815, respectively in mouse plasma; 0.891, 0.830 and 0.725, respectively in rat plasma. The percentage remaining for BB102-citrate was 69.8%-98.2%, 63.6%-79.8%, 69.7%-74.7%, 50.2%-63.6% and 62.8%-73.3%, respectively, in mouse, rat, dog, monkey and human plasma following 18-hour incubation, indicating that BB102-citrate may be unstable in mouse, rat, dog, monkey and human plasma.  
Tissue distribution in SD **rats**: Following a single oral administration of BB102-citrate at 90 mg/kg in SD rats, BB102 was distributed rapidly in rat, the concentration of BB102 in all tissues reached a maximum at 30 min post-dose, except kidney and lung in males and ovary, spleen and small intestine in females reached a maximum at 2 h post-dose. BB102 was mainly distributed in gastrointestinal tract and liver; the exposures of BB102 in liver, small intestine and stomach in both sexes were higher than that in plasma; the exposures of BB102 in brain in both sexes, skeletal muscle and ovary in females, and epididymis in males were lower than that in plasma; the exposures of BB102 in other tissues were close to that in plasma. The obvious elimination trend of BB102 concentration in all tissues was observed at 24 h post-dose, and the concentration of BB102 in other tissues was lower than 15% of Cmax, except kidney (16.5%) and overy (17.5%) in female rats. Meanwhile, except for the three reproductive tissues (i.e., testis, epididymis and ovaries) evaluating the exposure in single sex only, the exposure of BB102 in all tissues of males was lower than that in females (the ratio between males and females was 0.209-0.886).
clinical trial protocol
metabolism

Metabolic stability in hepatocytes: BB102-citrate showed low intrinsic clearance in rat and human hepatocytes and moderate intrinsic clearance in mouse, dog and monkey hepatocytes. Identification of BB102 metabolite **in hepatocytes**: Eleven metabolites of BB102 citrate were detected in mouse, rat, dog, monkey and human incubation samples in total. Nine metabolites of BB102 citrate were detected in mouse and rat incubation samples. Six metabolites of BB102 citrate were detected in dog incubation samples. Ten metabolites of BB102 citrate were detected in monkey and human incubation samples. BB102 citrate was incubated with mouse, rat, dog, monkey and human hepatocytes for 4 hours, the percentage remaining of parent drug was 94.97%, 94.24%, 96.14%, 92.49% and 96.13%, respectively, and there was no metabolite with percentage of peak area ≥3.00%.
clinical trial protocol
excretion

Following oral administration of BB102-citrate in SD rats, the mean recovery of BB102 in urine and feces within 120 h post-dose were 0.212% and 8.81%, respectively; the recovery of BB102 in bile within 32 h post-dose was 2.47%; the total recovery of BB102 in urine and feces was 9.03%. Combined the results of metabolite identification in excretion samples to make a preliminary analysis of the mass balance, 18 and 20 metabolites were detected in urine and feces samples, respectively, calculated by the peak area normalization method of mass spectrum, the peak area percentage of metabolites were 37.24% and 41.69%, respectively (the peak area percentage of parent drug were 62.76% and 58.31%, respectively), and the total recovery of parent drug and metabolites of BB102 in urine and feces was 15.45%. However, the above area normalization method could only preliminarily evaluate the excretion ratio of parent drug and metabolites in biological samples because of the response differences of parent drug and metabolites in mass spectrum. It was speculated that BB102 had extensive metabolic transformation in rats, and that BB102 was eliminated from the body in various metabolic pathways besides the parent drug, of which De-methylation and Hydrogenation were the main metabolic pathways. Most of BB102 was excreted within 48 h post-dose, and the urine and feces excretion amount within 48 h post-dose were 98.4% and 99.4%, respectively, of the total excretion within 120 h post-dose. The bile excretion amount of BB102 in rats with bile drainage operation within 24 h post-dose was 86.3% of the total bile excretion amount within 32 h post-dose, indicating that most of BB102 excreted through bile was excreted within 24 h post-dose. The results of excretion study showed that BB102 and its metabolites were mainly excreted through feces following oral administration of BB102, and there was no gender difference in the excretion pathway.
clinical trial protocol
pk interactions

CYP phenotyping: CYP3A4 and CYP3A5 were the main CYP enzymes involved in the *in vitro* metabolism of BB102. Inhibition potential of BB102 against CYP450 enzyme and **time-dependent inhibition** potential of BB102 against CYP450 enzyme: BB102 had moderate inhibition against CYP2B6
(IC50 = 6.84 µM), and had no time-dependent inhibition potential over the concentration range of 0.15-50 μM. BB102-citrate had inhibitory effect with inhibition rate <50% on CYP2C8, CYP2C9, CYP2C19 and CYP3A at the high concentration (15 or 50 µM), and BB102-citrate had no timedependent inhibitory effect on CYP2C8 at 50 µM, while there may have nicotinamide adenine dinucleotide phosphate-dependent time-dependent inhibitory effect on CYP2C9, CYP2C19 and CYP3A (midazolam and testosterone used as substrates). BB102 had no inhibition against CYP1A2 and CYP2D6. Induction potential of BB102 against CYP450 enzymes (CYP1A2, CYP2B6 and CYP3A4): BB102 had no induction potential against CYP1A2 and CYP2B6 over the concentration range of 0.3-7 μM but may have induction potential against CYP3A4 at the concentration of 7 μM. Over 24-h incubation, the data suggested that BB102 may be metabolized by human primary hepatocytes. Substrate and inhibition potential of efflux transporter: BB102-citrate was a substrate of P- glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and BB102-citrate had the inhibitory effect on P-gp at 7.5 μM and BCRP at >0.75 μM (Inhibition rate <50%). Substrate and inhibition potential of solute carrier transporter: BB102-citrate was not a substrate of SLC transporters OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1 or MATE2-K; BB102-citrate was an inhibitor of OAT1, OAT3, OATP1B3, MATE1 and MATE2-K transport.
clinical trial protocol
1.5.3 toxicology

BB102 was evaluated in a series of non-GLP and GLP nonclinical toxicology studies, including single and repeated dose toxicity studies. In the two nonclinical species (rats and dogs), BB102 showed similar toxicity profiles with repeated 28-day dosing. Adverse drug reactions (ADRs) of BB102 occurred mainly in the liver.
clinical trial protocol
single-dose toxicology studies

Single-dose toxicology study **in SD rats (non-GLP):** There were 18 SD rats (half males, half females), with a single dose via oral administration at 100, 300 and 1000 mg/kg of BB102-citrate [the vehicle was 0.5%MC (w/v) in citric acid solution]. All animals survived to the scheduled sacrifice day and the toxicity was obviously noted in animals given 1000 mg/kg. Abnormal clinical observations included hunched posture, decreased activity, wheeze, red staining of nose and deep breathing; decreases of body weight and body weight gain. Therefore, the MTD of SD rats was defined at 1000 mg/kg. Single-dose toxicology **study in Beagle dogs (non-GLP):** There were 2 Beagle dogs (1 male, 1 female), with a single dose via oral administration at 50, 100, 300 and 1000 mg/kg of BB102citrate [the vehicle was 0.5%MC (w/v) in citric acid solution] that the animals were well tolerated after observations for four days. Test article-related clinical observation was limited to emesis and abnormal feces (soft stool, loose feces and watery feces) and no body weight changes were noted. Therefore, the MTD of Beagle dogs was defined at 1000 mg/kg.
clinical trial protocol
repeat-dose toxicology studies

The 14-day dose range finding toxicity study in SD rats (non-GLP): SD rats were administered with vehicle and BB102-citrate at dose levels of 50, 150 and 500 (Day 1-Day 7)/300 (Day 8-Day 14) mg/kg/day [the vehicle was 0.5%MC (w/v) in citric acid solution, pH≈2.5] via oral gavage QD
for 14 days, in which the obviously toxicity was noted at dose level of 500/300 mg/kg/day. Eight animals were found dead (4 main study animals, including 2 males and 2 females and 4 toxicokinetics animals, including 1 male and 3 females) when given 500 mg/kg/day, and no animal dead was noted when dose level adjusted to 300 mg/kg/day. BB102-citrate-related alterations included: abnormal clinical observations (hunched posture, decreased activity and red staining of nose); decreases of body weight gain and food consumption; alterations of clinical chemistry [increases of alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL), decreases of blood urea, blood urea nitrogen/creatinine and fasting plasma glucose (GLU)]; alterations of hematology [decreases of haematocrit (HCT), hemoglobin (Hb), mean erythrocyte volume and mean erythrocyte red protein content, increases of absolute reticulocyte count (ABRETIC), white blood cell (WBC), absolute neutrophilic granulocyte count and absolute lymphocyte count (ABLYMP)]; alterations of coagulation (shorten activated partial thrombin time and prothrombin time); alterations of organ weight (increase in organ weight of heart, kidney and liver, decrease in organ weight of thymus, epididymis and uterus); macroscopic findings that diffuse yellowish discoloration of all lobes of liver. Therefore, the repeat dose MTD of SD rats was defined at 300 mg/kg/day in male and female animals, which corresponded to mean Cmax and AUClast values of 14200 ng/mL and 176723 h*ng/mL in males on Day 14, respectively. No Cmax and AUClast values of BB102-citrate in females were collected on Day 14 due to all toxicokinetics animals were dead. The 28-day oral toxicity and toxicokinetic study of BB102-citrate with a 28-day recovery period in SD rats (GLP): SD rats were administered with vehicle and BB102-citrate at dose levels of 50, 150 and 300 mg/kg/day [the vehicle was 0.5%MC (w/v) in citric acid solution, pH≈2.5] via oral gavage QD for 28 days; the reversibility, progression and/or potential delayed effects were investigated during a 28-day recovery period. One female animal at high-dose group (300 mg/kg/day) was found dead on Day 13, while other animals were well tolerated. No BB102-citraterelated findings in ophthalmology examination, coagulation parameters or urinalysis parameters were noted in the study. **BB102-citrate-related clinical symptom** was red staining of nose and right eye (female animals given 300 mg/kg/day). No abnormal findings were noted in recovery phase. **For body weight and food consumption,** in dosing phase, mean body weight and body weight gain of male animals given 300 mg/kg/day were lower than that of concurrent vehicle group, and mean body weight gain of female animals given 300 mg/kg/day was significantly lower than that of concurrent vehicle group. Minimal decrease of mean food consumption was noted in male and female animals given 300 mg/kg/day when compared with concurrent vehicle group. During recovery phase, the body weight and food consumption of male and female animals in each dose group showed recovery. **BB102-citrate-related alterations in clinical chemistry parameters** included: at terminal sacrifice, increase in ALP in females and males given 300 mg/kg/day; increase in TBIL in males given 300 mg/kg/day and females given ≥50 mg/kg/day; increases in blood urea, blood urea nitrogen/creatinine ratio and triglycerides and decrease in GLU in females given 300 mg/kg/day; decrease in cholesterol in two females given 300 mg/kg/day. The alteration of TBIL in females given ≥150 mg/kg/day was considered adverse. At recovery sacrifice, all alterations in clinical chemistry parameters at terminal sacrifice were completely reversed. BB102citrate-related alterations in hematology parameters included: at terminal sacrifice, consisted of minimal decrease in red blood cell (RBC) in females and males given ≥150 mg/kg/day; minimal decreases in HCT and Hb in males given 300 mg/kg/day and in females given ≥150 mg/kg/day; decreases in WBC and ABLYMP in females given 300 mg/kg/day. At recovery sacrifice, all alterations in hematology parameters at terminal sacrifice were completely reversed. BB102citrate-related alterations in organ weights included: at terminal sacrifice, BB102-citraterelated differences in organ weights included increases in absolute and relative (to brain and body weight) weights of the liver in females and males given ≥150 mg/kg/day; decreases in absolute and relative (to brain and body weight) weights of the thymus in females given 300 mg/kg/day. At recovery sacrifice, all alterations in organ weights at terminal sacrifice were completely reversed. BB102-citrate-related macroscopic observations noted in the liver, kidney and adrenal gland included: at terminal sacrifice, diffuse or multifocal yellowish discoloration of all lobes of the liver in females given ≥150 mg/kg/day and males given 300 mg/kg/day; diffuse or multifocal yellowish discoloration in the cortex of kidney in females given 300 mg/kg/day; multifocal dark red discoloration in the cortex of adrenal gland in 2 females given 300 mg/kg/day. At recovery sacrifice, all macroscopic observations at terminal sacrifice were completely reversed. **BB102-** citrate-related microscopic observations noted in the liver, kidney, thymus, pancreas and mandibular salivary gland in females and males, and in the adrenal gland in females included: at terminal sacrifice, minimal to moderate periportal hepatocyte vacuolation in the liver in females and males given ≥50 mg/kg/day; minimal or mild tubular vacuolation of the cortex and outer stripe of outer medulla in the kidney in females given 150 mg/kg/day as well as in females and males given 300 mg/kg/day; minimal or mild tingible body macrophage increase in the cortex of thymus in males given ≥ 150 mg/kg/day and females given ≥ 50 mg/kg/day; minimal and/or mild acinar cell secretory depletion in the pancreas in males given 50 mg/kg/day and 300 mg/kg/day and females given ≥ 50 mg/kg/day; minimal acinar cell hypertrophy in the mandibular salivary gland in females and males given 300 mg/kg/day; and minimal or mild zona fasciculata congestion/hemorrhage/necrosis in the unilateral or bilateral adrenal gland(s) in 4 females given 300 mg/kg/day. The moderate periportal hepatocyte vacuolation in the liver in females given ≥150 mg/kg/day at terminal sacrifice were considered adverse. At recovery sacrifice, all microscopic observations except for the change in the liver in males and females given ≥ 150 mg/kg/day at terminal sacrifice had completely reversed. Both on Day 1 and Day 28, the mean values of Cmax and AUClast in male animals were slightly less than female animals (Ratio: 0.496-0.876), except that the mean values of AUClast in male animals were closed to female animals (Ratio: 1.10) in 150 mg/kg/day dose group on Day 28. The male/female ratio of Cmax and AUClast decreased with the increase of dose level on Day 1. On Day 1 and Day 28, mean values of Cmax and AUClast in male and female increased in a close to or less than dose proportional manner in all dose group (ratio of 50-150 mg/kg/day: 1.53-2.91; ratio of 150-300 mg/kg/day: 1.22-2.20), except that mean values of Cmax in male were slightly decreased in the range of 150-300 mg/kg/day on Day 1 (Ratio: 0.941) and mean values of AUClast in male increased in a more than dose proportional manner in the range of 50-150 mg/kg/day on Day 28 (Ratio: 4.32). No accumulation of AUClast was observed after 28 days of repeat dosing in both male and female animals at all doses (ratio: 0.662-1.26 <2fold). Except for increase of TBIL and moderate periportal hepatocyte vacuolation in the liver in females given ≥ 150 mg/kg/day at terminal sacrifice, none of other findings were considered adverse. Therefore, the severely toxic dose to 10% of the animals (STD10) in this study was 300 mg/kg/day, which corresponded to mean Cmax and AUClast values of 15925 ng/mL and 165393 h*ng/mL in males, respectively, and 27275 ng/mL and 247610 h*ng/mL in females, respectively, on Day 28. The main toxic target organ was liver, and the liver related adverse changes exhibited signs of recovery during the recovery phase. The 14-day dose range finding toxicity study of BB102 in Beagle dogs (non-GLP): Beagle dogs were administered with vehicle and BB102-citrate at dose levels of 40, 100 and 200 mg/kg/day [the vehicle was 0.5%MC (w/v) in citric acid solution, pH≈2.5] via oral gavage QD for 14 days in which the main toxicity was noted at 200 mg/kg/day. BB102-citrate-related abnormal findings included: abnormal clinical observations (emesis, tremor, salivation, loose feces and watery feces); body weight loss; alterations of clinical chemistry parameters (increases of ALT, ALP, blood urea, blood urea nitrogen/creatinine, creatinine and phosphorus/P, and decreases of cholesterol, TG, sodium/Na, potassium/K and chlorine/Cl); alterations of organ weight (the weight of heart, kidney, liver, spleen and thymus decreased); macroscopic findings (decreased in size of thymus and spleen, multifocal dark red discoloration of mesenteric lymph, diffuse yellowish discoloration of all lobes of liver). Therefore, the repeat dose MTD of BB102-citrate was defined at 200 mg/kg/day in male and female animals, which corresponded to mean Cmax and AUClast values of 19500 ng/mL and 73131 h*ng/mL in males, respectively, and 12800 ng/mL and 122202 h*ng/mL in females on Day 14, respectively. The 28-day oral toxicity and toxicokinetic study of BB102-citrate with a 28-day recovery period in **Beagle dogs (GLP):** Beagle dogs were administered with vehicle and BB102-citrate at dose levels of 40, 100 and 250 mg/kg/day (the vehicle was 0.5%MC in citric acid solution, pH≈2.5) via oral gavage QD for 28 days; the reversibility, progression and/or potential delayed effects were investigated during a 28-day recovery period. One female given 250 mg/kg/day was sacrificed on Day 24, while other animals were well tolerated. No BB102-citrate-related changes were noted in ophthalmic examination, body temperature, blood pressure, coagulation parameters or urinalysis parameters. In dosing period, **BB102-citrate-related abnormal clinical observations included:**
emesis and loose feces in both females and males given ≥40 mg/kg/day; salivation in males given ≥100 mg/kg/day and females given 250 mg/kg/day; feces with white foam in males given ≥40 mg/kg/day and females given 250 mg/kg/day; watery feces and color change of feces in mals given ≥40 mg/kg/day and females given ≥100 mg/kg/day. Above findings showed recovery during recovery phase. For **body weight**, in dosing period, the decreases of body weight and body weight gain were noted in females and males at each dose level with dose-dependency. During recovery phase, the body weight and body weight gain of females and males at each dose level showed recovery. For **food consumption**, in dosing period, the frequency of "poor" in female animals given 250 mg/kg/day was greater than that in control group. In recovery phase, the food consumption of females and males at each dose level recovered to the same level as that in control group which showed recovery. **For electrocardiogram,** in dosing period, increase of heart rate and decrease of RR interval in males given 250 mg/kg/day were observed on Day 1 when compared with the concurrent control group. At the terminal period (day 26), decrease of PR interval was noted in males given 100 mg/kg/day and 250 mg/kg/day. BB102-citrate-related alterations were comparable to concurrent control group and were comparable to pre-dose levels at the recovery period. **BB102-citrate-related alterations of clinical chemistry parmeters**
included: increases of ALT and phosphorus/P; decreases of cholesterol, TG and low density lipoprotein cholesterol (LDL) in females and males given ≥40 mg/kg/day; decrease of ALP in males given ≥40 mg/kg/day and 2 females given 100 mg/kg/day; decreases of total protein, albumin (ALB) and globulin (GLO) in males given ≥ 40 mg/kg/day and 1 female given 250 mg/kg/day; decrease of GLO in 1 female given 100 mg/kg/day; increase of TBIL in 1 female given 100 mg/kg/day and 1 male and 1 female given 250 mg/kg/day; decrease of high density lipoprotein cholesterol (HDL) in males given ≥ 40 mg/kg/day and females given ≥ 100 mg/kg/day. No BB102citrate-related alterations of clinical chemistry parmeters were noted at recovery sacrifice. BB102citrate-related alterations of hematology parmeters included: decreases of ABRETIC,
absolute eosinophil count (ABEOS) in females and males given ≥40 mg/kg/day; decreases of RBC,
HCT, Hb in males given ≥40 mg/kg/day and females given 250 mg/kg/day. No BB102-citraterelated alterations of hematology parmeters were noted at recovery sacrifice. **BB102-citraterelated alterations in organ weights included:** increases in absolute and relative (to brain and/or body weight) weights of the liver in females and males given ≥40 mg/kg/day; decreases in absolute and relative (to brain and body weight) weights of the thymus in males given ≥ 40 mg/kg/day, one female given 100 mg/kg/day and one female given 250 mg/kg/day. No BB102-citrate-related alterations of organ weight were noted at recovery sacrifice. BB102-citrate-related macroscopic observations included: decrease in size of the thymus in males given 250 mg/kg/day and females given ≥100 mg/kg/day; multifocal or diffuse yellow discoloration in all lobes of the liver in females given ≥40 mg/kg/day. No BB102-citrate-related macroscopic findings were noted at recovery sacrifice. **BB102-citrate-related microscopic observations included:** minimal multifocal hepatocellular vacuolation in the liver and minimal and/or mild mucosal atrophy in the cecum, colon and rectum in both females and males given ≥40 mg/kg/day; moderate diffuse hepatocellular vacuolation in the liver in females given ≥100 mg/kg/day; minimal mucosal hyperplasia in the gallbladder and minimal and/or mild hypertrophy of follicular cell in the thyroid in both females and males given 250 mg/kg/day; minimal atrophy of acinar cell in the lacrimal gland, minimal and/or mild cortical and medullary lymphoid depletion in the thymus in males given ≥40 mg/kg/day and females given ≥100 mg/kg/day; minimal lymphoid depletion of white pulp in the spleen and minimal secretory depletion of acinar cell in the pancreas in females given 100 mg/kg/day; mild lymphoid depletion of gut associated lymphoid tissue in the ileum in females given 250 mg/kg/day; minimal atrophy of acinar cell in the mandibular salivary gland in females given ≥40 mg/kg/day; minimal epidermal atrophy and minimal adnexal atrophy in females given
≥100 mg/kg/day. The moderate diffuse hepatocellular vacuolation in liver in females given ≥ 100 mg/kg/day was considered adverse. No BB102-citrate-related microscopic findings were noted at recovery sacrifice. In the 40 mg/kg/day dose group and 100 mg/kg/day dose group, the values of Cmax and AUClast in males were closed to females on Day 1 and Day 28 (Ratio: 0.704-1.16), indicating there was no significant sex differences between males and females. In the 250 mg/kg/day dose group, the AUClast on Day 1 and Day 28 and the Cmax on Day 28 in males were slightly lower than that in females (Ratio: 0.503-0.651). On Day 1 and Day 28, Cmax and AUClast did not increase significantly or decreased in both females and males in the dose range of 40-100 mg/kg/day (Ratio: 0.759-1.29). Cmax and AUClast increased in the dose range of 100-250 mg/kg/day on Day 1 and Day 28 in both females and males in a manner close to or below the dose ratio increases (Ratio: 1.07-2.50). Compared to AUClast on Day 1, no significant accumulation of AUClast was observed in females and males in the 40 mg/kg/day dose group on Day 28 (Ratio: 1.56-1.96), and accumulation was observed in females and males in the 100 mg/kg/day and 250 mg/kg/day dose groups (Ratio: 2.17-3.00). The moderate diffuse hepatocellular vacuolation in the liver in females given ≥100 mg/kg/day was considered as adverse changes. The highest nonseverely toxic dose (HNSTD) for males and females was defined as 250 mg/kg/day and 100 mg/kg/day, respectively, which corrensponded to mean Cmax and AUClast values for BB102 of 12620 ng/mL and 65467 h*ng/mL in males, and 10166 ng/mL and 51999 h*ng/mL in females on Day 28, respectively. The main toxic target organ was liver, and the liver related adverse changes had completely reversed during the recovery phase.
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1.6 overview of clinical trials

BB102 belongs to the innovative drug/molecular, and there is no clinical trial data yet. Its preparation BB102 tablets have not been clinically investigated around the world, and this is the first clinical trial application in the United States of America.
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1.7 risk-benefit assessment

In order to meet the clinical treatment needs of FGF19 or FGFR4-positive advanced primary HCC or other advanced solid tumors as soon as possible and fill the gap in this treatment field, the sponsor applies for a phase I clinical trial to evaluate the safety, tolerability, PK profiles and efficacy of oral BB102 tablets in patients with advanced solid tumors on the basis of nonclinical studies. The risks and benefits of BB102 tablets will be assessed based on the mechanism of action of BB102, the nonclinical study data of BB102, and the clinical trial data of similar drugs.
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risks

The results of the safety pharmacology showed that BB102 was expected to have no adverse effects on the cardiovascular system, respiratory system, or central nervous system in humans.  
The 28-day oral toxicity study of BB102-citrate in SD rats: No BB102-citrate-related findings in ophthalmology examination, coagulation parameters or urinalysis parameters were noted in the study. Increase in TBIL and moderate periportal hepatocyte vacuolation in the liver in females given ≥150 mg/kg/day were considered adverse changes, and the main toxic target organ was liver.  
The 28-day oral toxicity study of BB102-citrate in Beagle dogs: No BB102-citrate-related changes were noted in ophthalmic examination, body temperature, blood pressure, coagulation parameters or urinalysis parameters. The moderate diffuse hepatocellular vacuolation in the liver in females given ≥100 mg/kg/day was considered as adverse changes, and the main toxic target organ was liver. In clinical trials of similar drugs (FGF401, BLU-554, H3B-6527), the most common AEs were diarrhea, asthenia, pyrexia, vomiting and nausea. By referring to the above information, in order to minimize the risk of the subjects, this trial will include the appropriate subject population through the inclusion/exclusion criteria, and ensure the safety of subjects through various safety examinations during the trial [hematology, urinalysis, fecal analysis, blood biochemistry, coagulation function test, vital signs examination, electrocardiogram examination, echocardiography examination, physical examination, Eastern Cooperative Oncology Group (ECOG) evaluation, pregnancy-related tests, etc.], AE treatment, dose interruption, dose adjustment and other measures. In addition, this trial will pay close attention to AEs and SAEs, as well as excessive bile acid levels in the blood and hepatobiliary diseases associated with hypersecretion of bile acids that occur or worsen in the trial to detect and deal with safety issues.
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benefits

BB102 tablets are an FGFR4 inhibitor with clear mechanism of action, high target selectivity and high drug activity. Nonclinical *in vitro* pharmacodynamic studies showed that BB102 was a strong FGFR4 inhibitor, and its inhibitory effect on FGFR4 kinase was better than BLU-554. BB102 showed its antitumor effect *in vitro* by selectively inhibiting the binding of FGF19 and FGFR4, thereby inhibiting its downstream signal pathway, and then inhibiting the proliferation of solid tumor cell lines with FGF19/FGFR4 high-expression and Ba/F3 cell lines with FGFR4 mutations. Nonclinical *in vivo* pharmacodynamic studies showed that BB102-citrate significantly inhibited the growth of human hepatocellular carcinoma HuH-7 cell mouse xenografts at 30 mg/kg BID, 60 mg/kg BID and 90 mg/kg BID doses, and its antitumor effect was similar to that of positive control FGF401, and was significantly better than that of positive control sorafenib and BLU-554. BB102citrate significantly inhibited the growth of human hepatocellular carcinoma JHH-7 cell mouse xenografts with dose dependent manner at 10 mg/kg BID, 30 mg/kg BID, 60 mg/kg BID doses and at 60 mg/kg BID, 80 mg/kg BID doses, which was slightly better than positive control BLU- 554. BB102-citrate significantly inhibited the growth of human breast cancer MDA-MB-453 cells xenograft tumor in mice at 80 mg/kg BID dose. The antitumor effect of BB102 in this model was similar to that of positive control BLU-554. BB102-citrate significantly inhibited the growth of human rhabdomyosarcoma SJCRH30 cell mouse xenografts at 60 mg/kg BID dose. The antitumor effect of BB102 in this model was similar to that of positive control BLU-554. BB102 could inhibit the growth of subcutaneous xenograft tumor of human hepatocellular carcinoma Hep 3B cells in CB17.SCID mice with a dose-dependent manner at 5 mg/kg BID, 10 mg/kg BID and 30 mg/kg BID doses, and its inhibitory effect was close to that of positive control FGF401. At the same time, the PK study of tumor bearing mice in this model showed the plasma exposure of BB102 was positively correlated with its antitumor effect, and the drug concentration in plasma of tumorbearing mice was basically consistent with that in tumor. In addition, BB102 inhibited the FGF19/FGFR4 signal pathway, thereby inhibiting the phosphorylation of ERK, a key protein in the downstream MAPK signal pathway, and finally showed its antitumor effect. **In general, the**
inhibitory effect of BB102 on tumer was better than or close to that of the positive control drugs sorafenib and BLU-554, and similar to that of the positive control drug FGF401. Among similar drugs, only FGF401, BLU-554, and H3B-6527 have clinical trial results published.  
In a phase I dose-escalation study of **FGF401 monotherapy** (N=74, FGFR4- and KLB-positive HCC or other advanced malignant solid tumors that progressed after standard therapy, were intolerable to standard therapy, or had no standard therapy available), the overall ORR was 5.4%
(4/74), and the DCR was 45.9% (34/74) [14]; in phase II dose expansion cohort 1 of FGF401 monotherapy (N=30, HCC patients from Asian countries; 120 mg QD fasted), the ORR was 6.7%
(2/30) and the DCR was 43.3% (13/30); in phase II dose expansion cohort 2 of FGF401 monotherapy (N=36, HCC patients from non-Asian countries; 120 mg QD fasted), the ORR was 5.6% (2/36) and the DCR was 61.1% (22/36); in phase II dose expansion cohort 3 of FGF401 monotherapy (N=20, patients with other malignant solid tumors, regardless of their geographic location; 120 mg QD fasted), the ORR was 0% and the DCR was 30% (6/20) [14]. Among 66 subjects with FGF19 IHC+ receiving **BLU-554 monotherapy**, 11 (17%) subjects were assessed to have an objective response, including 1 (2%) subject with CR and 10 (15%) subjects with PR; the mDOR was 5.3 months; the mPFS was 3.3 months (2.1-3.7 months). Among 34 subjects with FGF19 IHC-negative or unknown FGF19 status, the ORR was 0.0% [15]. After **H3B-6527**
monotherapy was given to HCC subjects who had previously received >2-line treatment receiving, the OS of QD administration (48 subjects) was 10.6 months, the PFS was 4.1 months, the total response rate was 16.7% (all PR), and the clinical benefit rate was 45.8% (response + stable disease for >17 weeks) [16].  
Therefore, it is estimated that BB102 tablets have good efficacy for FGF19 or FGFR4 positive advanced primary HCC or other advanced solid tumors.
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risk-benefit assessment

Based on the above-mentioned mechanism of action of BB102, the nonclinical study data of BB102, and the clinical trial data of similar drugs, the possible clinical benefits of BB102 tablets outweigh the potential risk of toxicity. The successful development of BB102 will further meet the urgent clinical needs of tumor patients, be of great clinical significance and bring economic and social benefits. Since this trial is an early phase trial of BB102 tablets, the suitable subject population will be included based on the inclusion/exclusion criteria; potential risks suggested by nonclinical studies have all been monitored and controlled in the clinical protocol; the safety of subjects will be ensured through AE treatment, dose interruption, dose adjustment and other measures; close attention will be paid to AEs and SAEs.
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2. study objectives 2.1 dose

To evaluate the safety and tolerability of different doses of BB102 tablets monotherapy (fasted or fed) in patients with advanced solid tumors.  
To explore the MTD by observing the DLT of BB102 tablets monotherapy (fasted or fed)
within the specified dose range, so as to provide rationale for determining the RP2D.
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secondary objectives

To investigate the PK profiles of BB102 tablets monotherapy (fasted) administered as single and multiple oral doses in patients with advanced solid tumors.  
To preliminarily investigate the effect of food on the PK profiles of BB102 tablets monotherapy administered as single and multiple oral doses in patients with advanced solid tumors.  
To preliminarily investigate the efficacy of BB102 tablets monotherapy (fasted or fed) in patients with advanced solid tumors.  
To investigate the relationship between biomarker and efficacy and to preliminarily infer the correlation.  
To explore the correlation between plasma concentration of study drug and Fridericia method corrected QT interval (QTcF) (C-QTcF analysis).  
To identify the metabolites of BB102 in patients with advanced solid tumors.
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2.2 expansion trial primary objectives

To evaluate the efficacy of BB102 tablets monotherapy (fasted) in patients with FGF19 or FGFR4 positive advanced primary HCC or other advanced solid tumors.
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secondary objectives

To investigate the PK profiles of BB102 tablets monotherapy (fasted) in patients with FGF19 or FGFR4 positive advanced primary HCC or other advanced solid tumors.  
To investigate the safety of BB102 tablets monotherapy (fasted) in patients with FGF19 or FGFR4 positive advanced primary HCC or other advanced solid tumors.  
To investigate the relationship between biomarker and efficacy and to preliminarily infer the correlation.
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3. selection and withdrawal of

Patients must meet all of the following criteria before being enrolled in the study:
(1) 18-78 years of age (inclusive) in dose escalation trial and ≥18 years of age in expansion trial at the time of signing the informed consent form (ICF), male or female.  
(2) For the dose escalation trial, histologically, cytologically confirmed or clinically confirmed advanced solid tumors patients who without available standard treatment, failed in standard treatment or cannot tolerate standard treatment (primary HCC patients are preferred; primary HCC patients should have a liver function score of ≤9 points as assessed according to the Child-Pugh classification criteria). Note: Only primary liver cancer can be clinically diagnosed, and other tumors need to be confirmed by histology or cytology. For the expansion trial, histologically or cytologically confirmed FGF19 or FGFR4 positive advanced primary HCC (primary HCC patients should have a liver function score of ≤9 points as assessed according to the Child-Pugh classification criteria) or other advanced solid tumors patients who without available standard treatment, failed in standard treatment or cannot tolerate standard treatment. Note: FGF19 or FGFR4 positivity includes but is not limited to FGF19 amplification, FGF19 overexpression, elevation of serum FGF19 protein level, FGFR4 amplification, FGFR4 overexpression and FGFR4 activating mutation. At the discretion of the investigator, the patien's previous positive test results for FGF19 or FGFR4 can be accepted (patients must agree to provide previous positive test results for FGF19 or FGFR4). Newly reported FGF19 or FGFR4 positive test results from a central laboratory based on tumor tissue and/or blood samples are also acceptable (patients must agree to provide tumor tissue samples and/or blood samples for FGF19 or FGFR4 positive testing. If there are special circumstances such as the tissue is difficult to obtain or the risk of obtaining biopsy is high, etc., the investigator can communicate with the sponsor to discuss whether it can be exempted. Tumor tissue: During screening period, tumor tissue samples from patients in the past 2 years or fresh tumor tissue samples can be collected; the samples can be collected from the primary lesion or metastatic lesions. Blood: A fresh blood sample 5 mL can be collected during the screening period).  
(3) For the dose escalation trial, at least one evaluable tumor lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix I). For the expansion trial, at least one measurable tumor lesion according to RECIST v1.1.  
(4) Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1 (Appendix II). (5) Life expectancy of ≥3 months. (6) With good organ function, including:  
➢ Liver function: TBIL ≤1.5 × upper limit of normal (ULN), ALT ≤3×ULN, and AST ≤3×ULN
(for patients with liver cancer or liver metastases, the criteria will be TBIL ≤3×ULN, ALT ≤5×ULN, and AST ≤5×ULN);
➢ Renal function: blood creatinine ≤1.5×ULN and creatinine clearance rate ≥50 mL/min
(calculated based on Cockcroft-Gault formula);
➢ Hematology (no blood transfusion or hematopoietic stimulating factor therapy within 14 days of blood sampling for hematology): blood platelet (PLT) ≥100×109/L (for patients with liver cancer, the criteria will be PLT ≥85×109/L), absolute neutrophil count (ANC) ≥1.5×109/L,
and Hb ≥90 g/L (90 mg/mL);
➢ Coagulation function: activated partial thromboplastin time ≤1.5×ULN and international normalized ratio ≤1.5×ULN.
(7) For female patients of childbearing potential, the pregnancy test result within 7 days before the first dose is negative and promise to use adequate and effective methods of contraception or abstinence from the start of screening period to 6 months after the last dose of study treatment; male patients who promise to use adequate and effective methods of contraception or abstinence from the start of screening period to 6 months after the last dose of study treatment. The definition of female with childbearing potential and contraceptive requirements are detailed in Appendix III.  
(8) Voluntarily participate in this clinical study, understand the content of the ICF and sign it voluntarily, with good compliance.
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3.2 exclusion criteria

Patients who meet any of the criteria cannot be enrolled in this study:
(1) Use of systemic immunosuppressive or systemic cortisol (≥10 mg prednisone or other equivalent hormone) within 4 weeks prior to the first dose.  
(2) Prior use of selective FGFR4 inhibitor and/or pan-FGFR inhibitor therapy.  
(3) Use of cytotoxic chemotherapeutics within 4 weeks prior to the first dose, OR use of stateapproved Chinese traditional patent drugs/Chinese traditional drugs with an anti-tumor effect within 2 weeks prior to the first dose. Note: For mitomycin C or nitrosoureas, 6-week washout is required; for small molecule targeted drugs and oral fluorouracil drugs, a washout period of 2 weeks or five T1/2 of the drug (whichever is longer) is required.  
(4) Anti-tumor endocrine therapy, radiotherapy, interventional embolization, radiofrequency, proton therapy, radioimmunotherapy, immunotherapy or other biotherapies within 4 weeks prior to the first dose (if five T1/2 of the drug/therapy used by the patient is confirmed to be <4 weeks, five T1/2 shall prevail).  
(5) Use of other clinical investigational drug or therapy that not marketed within 4 weeks prior to the first dose.  
(6) Patient is receiving drugs or therapies prohibited in the protocol (e.g., strong CYP3A4 inhibitors, strong CYP3A4 inducers, strong CYP3A5 inhibitors, strong CYP3A5 inducers, sensitive CYP3A4 substrates with a narrow therapeutic index, sensitive CYP2B6 substrates with a narrow therapeutic range, etc., see Section 6.2 of the main text for details) and cannot discontinue such use at least 2 weeks prior to the first dose or throughout the study.
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(7) pregnant or lactating females.

(8) Patient with known hypersensitivity to any ingredient of BB102 tablets, or patient who have a history of drug allergy and is judged as not suitable for participating in this study by the investigator.  
(9) Presence of clinically significant gastrointestinal disorder that may affect the intake, transport or absorption of study drugs (e.g., dysphagia, uncontrollable nausea and vomiting, active gastric ulcer, ulcerative colitis, Crohn's disease, chronic diarrhea, intestinal obstruction, and other conditions determined by the investigator that may cause gastrointestinal bleeding, perforation, etc.) at screening.  
(10) Patient with concurrent cancer (adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease recurrence, except carcinoma in situ) within 5 years prior to the first dose.  
(11) Adverse reaction of the prior anti-tumor therapy not yet recovered to grade ≤1 as assessed by CTCAE v5.0 at screening (except the toxicities that are judged as having no safety risk by the investigator, such as alopecia, asthenia, γ-glutamyltransferase (GGT) increased, ALP increased, grade 2 peripheral neurotoxicity, thyroid function decreased stabilized by hormone replacement therapy, etc.).  
(12) Clinically uncontrollable third space effusion at screening, which, at the investigator's discretion, is not suitable for enrollment. Note: For patients with third space effusion (pleural ascites, pericardial effusion) who are stable after local drainage and drug infusion, and drug-eluted for at least five T1/2 or 14 days (whichever is shorter), they can be considered for enrollment.  
(13) Presence of clinically symptomatic metastases to central nervous system or meninges or other evidence showing that metastatic lesions in central nervous system or meninges have not yet been controlled at screening, which, at the investigator's discretion, is not suitable for enrollment. Note: Patients with central nervous system metastases or meningeal metastases who are asymptomatic or in a stable state after treatment before the first dose can be considered for enrollment.  
(14) History of severe neurological or psychiatric disorders, including epilepsy, dementia, or moderate to severe depression, etc.  
(15) History of drug abuse or dependence.  
(16) Clinically significant and uncontrolled cardiovascular diseases, including:  
➢ Serious cardiac rhythm or conduction abnormality at screening, such as ventricular arrhythmia that requires clinical intervention, second/third-degree AV block, etc.;
➢ Myocardial infarction within 12 months prior to the first dose;
➢ Acute coronary syndrome, congestive cardiac failure, aortic dissection, cerebral stroke or other grade ≥3 cardiovascular and cerebrovascular events within 6 months prior to the first dose;
➢ Arterial or deep venous thrombosis within 6 months prior to the first dose, or those who need to monitor international normalized ratios or use anticoagulants at screening. Note: Patients with superficial venous thrombosis which do not need treatment can be considered for enrollment; patients who can stop anticoagulant within 2 weeks before the first dose and during the administration period can be considered for enrollment;
➢ Mean resting QTcF >480 ms at screening, which are obtained from three 12-lead electrocardiograms (ECGs) [Note: QTcF is calculated based on Fridericia formula, QTcF = QT/(RR^0.33)];
➢ Heart failure of New York Heart Association Class ≥II at screening;
➢ Left ventricular ejection fraction (LVEF) <50% at screening;  
➢ Hypertension (defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure
≥100 mmHg) that medication fails to control stably at screening;
➢ Hyperglycemia that medication fails to control stably at screening.
(17) Pulmonary embolism within 6 months prior to the first dose, or interstitial pneumonia at screening.  
(18) Prior allogeneic stem cell transplantation, bone marrow transplantation or vital organ transplantation.  
(19) Surgical operation (excluding aspiration biopsy) of vital organs or significant trauma within 8 weeks prior to the first dose, or unrecovered surgical effect at screening, or planned elective major surgery during the study period.  
(20) Presence of uncontrollable infectious disease, congenital immunodeficiency disease, acquired immunodeficiency syndrome [positive for human immunodeficiency virus antibody (HIV-Ab)], syphilis (positive for syphilis antibody), active hepatitis B [for non-HCC patients, hepatitis B virus
(HBV)-DNA >500 IU/mL; for HCC patients, HBV-DNA >104copies/mL or 2000 IU/mL; hepatitis B patients need to take oral anti-HBV drugs regularly during the administration of BB102 tablets],
hepatitis C virus (HCV) infection (positive for HCV antibody, and positive for quantitative detection of HCV ribonucleic acid amplification).  
(21) Severe active infection, including but not limited to bacteremia, severe pneumonia, etc.,
occurred within 2 weeks before the first dose; active infection that received therapeutic intravenous antibiotics within 2 weeks before the first dose.  
(22) Patient with active autoimmune disease, such as rheumatism, rheumatoid, etc. (23) The investigator considers that the patient is not suitable for participating in this study (e.g.,
study treatment is not in the best interest of patient, patients with mental disorder, patients with poor compliance, etc.).
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3.3 withdrawal of subjects

Subjects have the right to discontinue study treatment and/or withdraw from the trial for any reason at any time without affecting future treatment provided by the clinician or the study facility. The investigator also has the right to terminate the study treatment at any time during the study for reasons such as the subject's clinical condition, safety, compliance or management.
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criteria for study treatment discontinuation

Subject has disease progression, unless the investigator believes the subject can still benefit from the study treatment clinically.  
The investigator determines that the subject cannot clinically benefit from the study treatment and continued study treatment may pose an unacceptable risk to the subject.
There is major protocol deviation. After enrollment, the subject is found to be non-compliant with enrollment criteria in the study protocol or does not follow requirements in the study protocol, and the investigator believes that continued study treatment may pose an unacceptable risk to the subject.  
The subject has a poor compliance, uses prohibited concomitant medications without permission or fails to attend visits on schedule, which affects the evaluation of efficacy and/or safety, and the subject is considered inappropriate to continue the study at the discretion of the investigator.  
The subject experiences a particular comorbidity or complication, which, in the discretion of the investigator, makes it inappropriate to continue the study treatment.  
The subject experiences an intolerable toxicity.  
Subject pregnancy. Subject is lost to follow-up for more than 8 weeks.  
Subject death.  
Any other conditions in which the investigator believes that the study should be terminated.  
The subject refuses to continue the study treatment.  
The study site is closed prematurely, the study is prematurely terminated or the study ends.  
Notes: After study treatment discontinuation, subjects will enter into the follow-up period (unless follow-up is not applicable).
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handling of withdrawal/dropout subjects

Determination of dropout: All subjects who sign the ICF and are screened to be eligible to enter the trial have the right to withdraw from the trial at any time, regardless of the time and reasons. As long as they do not complete the entire clinical trial observation, they are all dropout subjects. Blood samples and tumor tissue samples already obtained from dropout subjects should be retained, processed, and tested. Subjects can withdraw from the trial without giving any reasons. While respecting the individual rights of the subjects, the investigator should try his best to understand the reasons for withdrawal, and fill in the reasons for withdrawal in the electronic Case Report Form (eCRF); make all possible efforts to contact the subject (if possible, the investigator should meet the subject in person) to complete the assessment items that can be completed, fill in the end of treatment follow-up record form, and record the time of last medication where possible. For those who withdraw due to an AE, the corresponding AE must be recorded in the eCRF. Subjects should return the remaining study drug to the study site. For subjects who withdraw from the trial due to any reason, their eCRFs should be retained; their last test results should be adopted as the final results; and all data on their efficacy and safety should be analyzed. All study treatment-related toxicities and SAEs ongoing at the time of study termination must be followed up until relieved, unless in the opinion of the investigator, the improvement of this condition is impossible due to the subject's existing condition.
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3.4 rescreening

Subjects who have failed the first screening can be re-screened (they must re-sign the ICF and be assigned a new screening number) at the discretion of the investigator. Subjects can be enrolled in the trial if they meet all the inclusion criteria specified in the protocol and do not meet any of the exclusion criteria at re-screening. Each subject is allowed to be re-screened once.
clinical trial protocol
4. overall study design 4.1

This study consists of a dose escalation trial and an expansion trial, both of which are designed as multi-center and open-label trials. This study aims to investigate the safety, tolerability, PK profiles and efficacy of BB102 tablets monotherapy (fasted or fed) orally administered at different doses in patients with advanced solid tumors and to evaluate the effect of food on the PK profiles.
clinical trial protocol
4.1.1 dose escalation trial (6

According to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)-S9 "*Guideline on Nonclinical Evaluation* for Anticancer Pharmaceuticals", a common approach for many small molecules anticancer drugs is to set a starting dose at 1/10 the STD10 in rodents of repeat-dose toxicity study; if the non-rodent is the most appropriate species, then 1/6 the HNSTD is considered an appropriate starting dose.  
According to the CDE "*Technical Guidelines for Clinical Trials of Anticancer Drugs*" and "Considerations for Starting Dose Calculation for Phase I Clinical Trial of New Anticancer Pharmaceuticals", in view of the ethical factors in tumor patients, 1/3 to 1/5 the no observed adverse effect level (NOAEL) is most commonly adopted for small molecule targeted anticancer pharmaceuticals. The corresponding human doses are calculated using the body surface area method based on the above parameters and nonclinical effective starting dose (see the following table). The female rat is the most sensitive species, and the corresponding maximum recommended starting dose (MRSD) is 107.4 mg/day based on the above parameters of nonclinical toxicology; the human equivalent dose calculated based on the nonclinical effective starting dose is 53.6 mg/day.  
Nonclinical Toxicology  
| Nonclinical Toxicology           | Reference  body  weight of  the  subject (kg)   | Alternative  human  MRSD (mg/day)   |                     |                            |                                    |
|----------------------------------|-------------------------------------------------|-------------------------------------|---------------------|----------------------------|------------------------------------|
| Dosage                           |                                                 |                                     |                     |                            |                                    |
| Animal/study                     | (mg/kg/day)                                     | Safety  factor                      | Calculation process |                            |                                    |
| Rats - 28 days QD - gavage - GLP | STD10: 300                                      | 60                                  | 10                  | 300/36.88*6.60*60/10=322.1 | 322.1 Male  1455.4; Female  582.2; |
| Beagle dogs -                    | 28                                              |                                     |                     |                            |                                    |
| days QD - gavage - GLP           | HNSTD:                                          | 250/36.88*21.47*60/6=1455.4;       |                     |                            |                                    |
| 60                               | 6                                               |                                     |                     |                            |                                    |
| Male 250;                        | 100/36.88*21.47*60/6=582.2                      |                                     |                     |                            |                                    |  
| Female 100  (deaths at  high dose) NOAEL:                                                            | Male 644.3;                                   |                                             |                     |                        |      |
|------------------------------------------------------------------------------------------------------|-----------------------------------------------|---------------------------------------------|---------------------|------------------------|------|
| 300/36.88*6.60*60/5=644.3;                                                                          |                                               |                                             |                     |                        |      |
| 60                                                                                                   | 5                                             | 50/36.88*6.60*60/5=107.4                    |                     |                        |      |
| Female 50;                                                                                           |                                               |                                             |                     |                        |      |
| Rats - 28 days QD - gavage - GLP                                                                     | Male 300;                                     | Female  107.4; Male  1746.5; Female  279.4; |                     |                        |      |
| Animal pharmacodynamic tumor model Beagle dogs - 28  days QD - gavage - GLP NOAEL:                   | 250/36.88*21.47*60/5=1746.5;                 |                                             |                     |                        |      |
| 60                                                                                                   | 5                                             | 40/36.88*21.47*60/5=279.4                   |                     |                        |      |
| Female 40; Male 250;                                                                                 | Reference  body  weight of  the  subject (kg) | Human  equivalent  dose (mg/day)            |                     |                        |      |
| Effective                                                                                            |                                               |                                             |                     |                        |      |
| Animal/study                                                                                         | dose (mg/kg)                                  | Safety  factor                              | Calculation process |                        |      |
| Nude mice - 21 days  BID - oral                                                                      | 5                                             | 60                                          | NA                  | 5*2/36.88*3.29*60=53.6 | 53.6 |
| Abbreviations: BID = twice daily; GLP = Good Laboratory Practice; HNSTD = highest non-severely toxic |                                               |                                             |                     |                        |      |  
Nude mice - 21 days  
BID - oral 5 60 NA 5*2/36.88*3.29*60=53.6 53.6  
Abbreviations: BID = twice daily; GLP = Good Laboratory Practice; HNSTD = highest non-severely toxic  
dose; MRSD = maximum recommended starting dose; NOAEL = noobservedadverseeffect level; QD = once  
daily; STD10 = severely toxic dose to 10% of animals.  
Note: The body surface area method is used for conversion, human dose (mg) = animal dose (mg/kg) ÷ (km  
human/km animal) * 60 kg; km human = 36.88; km dog = 21.47; km rat = 6.60 (body weight 200 g); km mice  
= 3.29.  
With the starting doses (e.g., 50, 60, 75, 140, 200, 300 mg/day), escalation doses (e.g., 50, 60, 75, 80, 100, 120, 150, 180, 200, 240, 250, 300, 320, 400, 450, 600, 800, 900, 1000, 1200, 1400, 1600, 2000, 2400 mg/day) and RP2D (e.g., 120, 600, 1000 mg/day) of similar drugs and strengths (10 mg, 50 mg) of BB102 tablets, this trial intends to use 50 mg as the starting dose.
clinical trial protocol
4.1.1.2 rationale for selection of

With a reference to the MTD of repeat-dose toxicity study (see the following table), MTD (e.g., 120 mg/day, 600 mg/day, MTD not reached) and RP2D (e.g., 120, 600 and 1000 mg/day) in the first-in-human study of similar drugs as well as the strengths (10 mg, 50 mg) of BB102 tablets, this study plans to adopt 420 mg as the maximum dose. Based on Fibonacci method, the proposed fasted escalation doses are: 50 mg QD, 100 mg QD, 160 mg QD, 240 mg QD, 320 mg QD and 420 mg QD.  
Nonclinical Toxicology  
| 1/2                                                                                                    | human                                       |                                 |                            |        |        |
|--------------------------------------------------------------------------------------------------------|---------------------------------------------|---------------------------------|----------------------------|--------|--------|
| equivalent  dose (mg/day)                                                                              |                                             |                                 |                            |        |        |
| Beagle dogs - longterm toxicity - 14  days QD - gavage - non-GLP                                                                                                        | Reference  body weight  of the subject (kg) | Human  equivalent dose (mg/day) |                            |        |        |
| Calculation  process                                                                                   |                                             |                                 |                            |        |        |
| Animal/study                                                                                           | MTD 200  mg/kg/day                          | 60                              | 200/36.88*21.47 *60=6985.9 | 6985.9 | 3493.0 |
| Rats                                                                                                   | -                                           | long-term                       |                            |        |        |
| toxicity -                                                                                             | 14 days                                     |                                 |                            |        |        |
| QD - gavage - nonGLP                                                                                                        | 300  mg/kg/day                              | 60                              | 300/36.88*6.60* 60=3221.3  | 3221.3 | 1610.6 |
| Note: The body surface area method is used for conversion, human dose (mg) = animal dose (mg/kg) ÷ (km |                                             |                                 |                            |        |        |  
Note: The body surface area method is used for conversion, human dose (mg) = animal dose (mg/kg) ÷ (km human/km animal) * 60 kg; km human = 36.88; km dog = 21.47; km rat = 6.60 (weight 200 g).  
Taking into account the human dose corresponding to the nonclinical effective starting dose (53.6 mg/day), the accelerated escalation (enrolling 1 subject only) of 50 mg enables quick escalation to the effective dose under the premise of guaranteeing the safety of subjects and subsequently avoids excessive exposure of subjects to ineffective doses. In addition, according to the action mechanism of FGFR4 inhibitors, inhibition of FGF19/FGFR4 signaling pathway will upregulate CYP7A1 expression (CYP7A1 is associated with metabolism of bile acid) and subsequently cause an increase in bile acid secretion; bile acid secretion also increases after meal. Dose escalation trial of the similar drug FGF401 (NCT02325739) set up separate fed dose escalation groups. Therefore, in order to investigate the effect of food on the safety and tolerability (primary), PK profiles (secondary) of BB102 tablets monotherapy, in this study, an appropriate dose will be selected as the fed dose escalation group according to the previously obtained clinical trial data of BB102 tablets.
clinical trial protocol
4.1.1.3 escalation method

This study adopts a modified 3+3 escalation design, including accelerated escalation and 3+3 escalation, with 6 fasted dose groups (50 mg QD, 100 mg QD, 160 mg QD, 240 mg QD, 320 mg QD and 420 mg QD) and 1 fed dose group. Note: Before the start of the dose escalation trial, the dosage of the fed dose group cannot be determined temporarily, and an appropriate dose will be selected subsequently by the safety monitoring committee (SMC) according to the previously obtained clinical trial data of BB102 tablets; the trial of the fed dose group can be synchronized with the dose escalation process of the fasted dose groups, and the trial of the fed dose group can also be started after the dose escalation of the fasted dose groups is completed, but the trial of the fed dose group must only be initiated after the equivalent dose is demonstrated to be safe under the fasted condition. The starting dose group (50 mg QD group) is the accelerated escalation group; other dose groups are 3+3 escalation groups. See Figure 1. All subjects enrolled will firstly receive a single dose for safety observation and PK study, and then undergo a 5-day washout period. Later, subjects will receive multiple-dosing to continue the safety observation and PK study. Multiple-dosing is tentatively scheduled as: once daily in 21-day cycles. After Cycle 1 is finished, a subject can continue to receive the next cycle of treatment if the investigator believes that the subject may benefit from the study treatment.  
 In order to avoid excessive exposure of subjects to ineffective doses, the accelerated escalation group (50 mg QD group) is planned to enroll 1 subject. The method for judging dose escalation is shown in Figure 2. During the DLT observation period (defined as the period from a single dose to the end of Cycle 1 of multiple-dosing), if there is no DLT or grade ≥3 drug-related toxicity [defined as an adverse event (AE) definitely/possibly related to the study drug], the enrollment of the next dose group will be started; if any DLT or grade ≥3 drug-related toxicity occurs, the group will be converted to the 3+3 escalation mode.  
  
It is planned to enroll 3 subjects to other groups, and the specific dose escalation method is shown in Figure 3. For each dose group, if none of the 3 subjects experiences DLT, the trial will proceed to the next dose group. If ≥2 out of the 3 subjects experience DLT, the dose escalation will be discontinued. If 1 of the 3 subjects experiences DLT, 3 additional subjects should be enrolled into this dose group (if none of the 3 newly enrolled subjects experiences DLT, the trial will proceed to the next dose group; If ≥1 of the 3 newly enrolled subjects experience DLT, dose escalation will be discontinued).  
  
The second and third subjects in the 3+3 escalation groups should only be enrolled after the first subject is observed for at least 5 days after dosing (enrolled on or after C1D1 of the first subject). If the previous subject experiences DLT, the sponsor and the investigator need to cautiously judge whether to enroll the next subject based on the safety data; if subsequent subjects have already been enrolled, the enrolled subjects should continue the study treatment (unless these subjects meet the criteria for study treatment discontinuation), with his/her safety data closely monitored. SMC will decide whether to perform dose escalation or reduction and determine whether to and how to adjust the escalation doses based on the safety, tolerability and/or PK data obtained during the DLT observation period of a certain dose group. Based on the safety, tolerability, PK and efficacy data of a certain group, if the investigator believes that it is necessary to expand the number of subjects of this dose group to further observe the safety and efficacy and obtain PK data, the number of subjects of this dose group may be increased to 4-12 after reaching a consensus with the sponsor through discussion. To ensure the safety of subjects, the washout time after single-dosing, dosing frequency, cycle setting, and time points of PK sample collection in the subsequent study as well as the design of subsequent escalation doses (e.g., adding dose groups of 520 mg QD and 600 mg QD) may be timely adjusted based on the previously obtained safety, tolerability, PK parameters [e.g., T1/2, drug accumulation after multiple-dosing] and other previously obtained clinical trial data of BB102 tablets. MTD is defined as the highest dose level in which DLT occurs in ≤1/6 of the total subjects during the DLT observation period. If MTD is not reached after administration of the maximum dose level shown above, the SMC will decide whether to increase dose groups based on the nonclinical data and the efficacy doses and PK parameters of domestic and foreign similar drugs observed in human.
clinical trial protocol
4.1.1.4 dlt definition

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

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

1) Grade ≥4 non-hematologic toxicity. Note: Toxicities with no safety risk at the discretion of the investigator are excepted, such as grade 4 GGT increased and alkaline phosphatase (ALP) increased. 2) Grade 3 non-hematologic toxicity (including but not limited to hepatobiliary disorders). Note: Toxicities with no safety risk at the discretion of the investigator (such as grade 3 nausea, vomiting, diarrhea, asthenia, constipation, loss of appetite, mucositis, GGT increased, ALP increased) are not defined as DLT, but they will be defined as DLT when the toxicities do not recover to grade ≤2 within 7 days under the circumstance of symptomatic supportive treatment are permitted.
clinical trial protocol
(3) other conditions

1) The grade is elevated from baseline with clinically significant and/or unacceptable toxicity, which is judged as a DLT by the SMC. 2) Drug discontinuation lasting 7 days or more due to drug-related toxicity. 3) The dose received by the subject during the DLT observation period is less than 75% of the scheduled dose due to toxicities attributable to study drug, and the investigator believes that it should be considered as a DLT.
clinical trial protocol
4.1.1.5 dlt evaluable subjects

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

The SMC should be composed of the sponsor (medical monitor, etc.), the investigator, the medical monitor of the Contract Research Organization (CRO), and other relevant personnel. The SMC meetings should be held as needed in the appropriate phase of the trial, e.g., before moving to the next dose group, when significant toxicity occurs, and after escalation to the maximum dose group. The SMC should discuss the obtained data such as subject safety, tolerability, PK, food effects, and preliminary efficacy through appropriate means (such as teleconferences, online conferences or emails, and if necessary, on-site meetings), and make a decision on whether to perform dose escalation or dose de-escalation, whether and how to adjust the escalation dose, whether to add dose groups, etc.
clinical trial protocol
4.1.2 expansion trial (expansion groups)

Based on the safety, tolerability, PK and efficacy data obtained in previous trials, 1 to 3 appropriate doses (e.g., 100 mg QD, 160 mg QD, and 240 mg QD) will be selected for the expansion trial. The expansion trial can be initiated when the above doses are demonstrated to have a favorable safety in the dose escalation trial (i.e., the number of subjects experiencing DLT in the group is ≤1/6 of total subjects of the group), without waiting for the completion of the entire dose escalation trial. Each expansion group will enroll 12 subjects to investigate the efficacy, safety and PK profiles of BB102 tablets. During the expansion trial, AEs meeting the definition of DLT will be regarded as AEs of special interest for safety assessment, thereby enriching the safety assessment data.
clinical trial protocol
4.2 randomization and blinding 4.2.1

Patients must sign the ICF before they can be screened. The screening number is "XXYYY", where "XX" is the study site number, and "YYY" is the patient's serial number for signing the ICF. The first subject of site 01 is 01001, the third subject of site 02 is 02003, and so on. If a patient fails screening or withdraws from the trial, the patient's screening number can no longer be used, and patients withdrew from the study can no longer participate in the trial.
clinical trial protocol
4.2.2 randomization method

This phase I trial is a non-randomized trial and no randomization will be performed.
clinical trial protocol
4.2.3 blinding

This phase I trial is an open-label trial involving dose escalation and expansion, and does not involve blinding.
clinical trial protocol
4.3 study procedures

Throughout the Phase I study, all subjects need to receive study treatment, safety assessment, PK blood sampling and efficacy evaluation according to the visit schedule. The tumor tissue specimens will be collected and preserved. For the specific collection, handling and storage methods, refer to the related standard operation procedure (SOP) of each study site. Computed tomography (CT) and other electronic documents should be saved on disc. All laboratory tests should be carried out in laboratories recognized by study sites. Normal ranges of all laboratory test items and the updates during the trial should be collected and preserved.  
If the investigator deems it necessary, each test item can be retested within the corresponding test time window and the retest data shall prevail.
clinical trial protocol
tumor assessment

1) Imaging tests like computed tomography (CT) /magnetic resonance imaging (MRI) and other radiological examinations of chest, upper abdomen, lower abdomen, pelvic cavity and other positions will be performed. For patients with suspected or known brain metastasis, a radiological examination must be performed at screening/baseline, and contrast-enhanced MRI is preferred (for those allergic to contrast medium, CT/MRI plain scan is acceptable). If brain metastasis is confirmed at screening, the frequency of brain CT/MRI in the subsequent cycles should be kept consistent with the tumor assessment frequency specified in the study; if it is confirmed that there is no brain metastasis by brain CT/MRI at screening, brain CT/MRI will be performed for confirmation if brain metastasis is suspected by the investigator later. For patients with bone metastasis symptoms, a bone scan must be performed at screening/baseline, and those with a positive result should receive contrast-enhanced MRI
scan at the corresponding position for further confirmation. If bone metastasis is confirmed at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if progression of the pre-existing bone metastasis or new bone metastasis is suspected by the investigator later; if it is confirmed that there is no bone metastasis at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if bone metastasis is suspected by the investigator later. Tumor assessments will be performed according to RECIST v1.1. Tumor markers: During the corresponding visits for imaging tests, 4 mL of peripheral blood will be collected for the detection of tumor biomarkers, such as liver cancer [alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA)], breast cancer [cancer antigen 15-3 (CA15-3)], ovarian cancer and endometrial cancer [carbohydrate antigen 125 (CA125)], prostate cancer [prostate specific antigen (PSA)], lung cancer [cytokeratin 19 fragment (CYFRA21-1)] and pancreatic cancer [carbohydrate antigen 242 (CA242)], which serve as auxiliary efficacy indicators.  
2) If a subject received a CT/MRI or other radiological examinations within 4 weeks prior to the first dose and has not received any anti-tumor therapy since this tumor assessment, and at the investigator's discretion, the tumor assessment can be performed according to RECIST v1.1, this examination result can be used as baseline tumor assessment result (repeated examination is not necessary).  
3) A tumor assessment will be performed at the end of Cycle 1, for which the time window is the end of the cycle ± 1 day. Thereafter, tumor assessments will be performed once every 2 cycles, for which the time window is the end of every 2 cycles ± 7 days [if a subject's assessment result is CR, PR or stable disease (SD), the subject can continue the treatment and continue to receive tumor assessments once every 2 cycles].  
4) The radiological confirmation examination of CR or PR should be completed 4-8 weeks after the first evaluation of CR or PR.
5) For the end of treatment visit (EOT), the investigator will determine whether a tumor assessment is required according to the actual condition. If a tumor assessment has been performed within 2 months prior to EOT, it is not necessary to repeat the tumor assessment at EOT visit.  
6) During the subsequent follow-up visits once every 8 weeks (±7 days) after the last dose, a tumor assessment will be performed for the subjects who are assessed as having no tumor progression in the previous assessment.
clinical trial protocol
4.3.1 screening period/baseline (d-28 to

Specific procedures and assessments are as follows:
➢ **Informed consent:** Subjects should sign an ICF before starting any study-related procedure.  
➢ **Demographics:** Age, gender, race and ethnicity. ➢ **Medical history and medication history:** History of all neoplastic diseases, history of all anti-tumor therapies, history of other diseases (within 6 months before enrollment and at present), history of other medications (within 6 weeks before enrollment and at present), family history, surgical history, allergic history, smoking history, history of drug abuse/dependence and history of menstruation and childbearing.  
➢ **Hematology:** RBC count, WBC count, absolute monocyte count (ABMONO), PLT count, ANC, ABLYMP, basophil count, ABEOS, ABRETIC, neutrophil ratio, Hb, HCT, mean corpuscular volume, and mean corpuscular hemoglobin concentration (MCHC). Hematology test at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.  
➢ **Urinalysis:** Potential of hydrogen (pH), specific gravity, urine RBC, urine WBC, urine glucose, urine bilirubin, urine protein, urobilinogen, urine ketone bodies, and urine occult blood. Urinalysis at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.  
➢ **Stool routine:** Color, shape, fecal RBC, fecal WBC, fecal occult blood, fecal choline, and fecal bilirubin. Stool routine test at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.
clinical trial protocol
blood biochemistry

1) **Liver function:** AST, ALT, ALP, LDH, GGT, TBIL, direct bilirubin, total bile acids, ALB,
total protein, and GLO.  
2) **Renal function:** Urea/urea nitrogen, creatinine, creatinine clearance, and uric acid.  
3) **Blood lipids:** Total cholesterol, HDL, low LDL, and TG. 4) **Electrolytes:** Potassium, sodium, chloride, phosphorus, magnesium, and calcium. 5) **Cardiac function:** Creatine kinase (CK) and creatine kinase isozyme (CKI).  
6) **Blood glucose**: GLU.  
Blood biochemistry test at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.  
➢ **Coagulation:** Prothrombin time, activated partial thromboplastin time, fibrinogen quantification, and international normalized ratio. Coagulation test at screening visit should be completed within 7 days prior to the first dose, and abnormal test parameters with clinical significance can be re-tested once within 7 days as needed.  
➢ **Vital signs:** Body temperature, blood pressure, heart rate, and respiration. Follow the visit time window.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. Follow the visit time window.  
➢ **Physical examination:** Assessments will be performed by organ and system. At screening, a comprehensive physical examination will be performed, including body height, body weight, body mass index (BMI), general condition, nervous system, head and neck, lymph nodes, skin, mucosa, chest, abdomen, four limbs and spine.
clinical trial protocol
ecog assessment. pregnancy-related tests

1) For women of childbearing potential, human chorionic gonadotropin (HCG) will be tested. Blood HCG pregnancy test at screening visit should be completed within 7 days prior to the first dose.  
2) For women ≥40 to <60 years of age and at least 12 months post-menopausal, follicle stimulating hormone, estradiol and luteinizing hormone will be tested; if necessary, antiMullerian hormone can be tested additionally. This test will be performed at screening only.  
3) For men and women ≥60 years of age, a pregnancy-related test is not required.
clinical trial protocol
echocardiography lvef.

➢ **Serum etiology test:** HIV-Ab, hepatitis B surface antigen (HBsAg), HBV-DNA (as needed),
hepatitis C virus antibody (HCV-Ab) and HCV-RNA (as needed). Serum etiology test at screening visit should be completed within 14 days prior to the first dose.
clinical trial protocol
tumor assessment

1) Imaging tests like CT/MRI and other radiological examinations of chest, upper abdomen, lower abdomen, pelvic cavity and other positions will be performed. For patients with suspected or known brain metastasis, a radiological examination must be performed at screening/baseline, and contrast-enhanced MRI is preferred (for those allergic to contrast medium, CT/MRI plain scan is acceptable). If brain metastasis is confirmed at screening, the frequency of brain CT/MRI in the subsequent cycles should be kept consistent with the tumor assessment frequency specified in the study; if it is confirmed that there is no brain metastasis by brain CT/MRI at screening, brain CT/MRI will be performed for confirmation if brain metastasis is suspected by the investigator later. For patients with bone metastasis symptoms, a bone scan must be performed at screening/baseline, and those with a positive result should receive contrast-enhanced MRI scan at the corresponding position for further confirmation. If bone metastasis is confirmed at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if progression of the pre-existing bone metastasis or new bone metastasis is suspected by the investigator later; if it is confirmed that there is no bone metastasis at screening, a bone scan or contrastenhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if bone metastasis is suspected by the investigator later. Tumor assessments will be performed according to RECIST v1.1. Tumor markers: During the corresponding visits for imaging tests, 4 mL of peripheral blood will be collected for the detection of tumor biomarkers, such as liver cancer (AFP, CEA), breast cancer (CA15-3), ovarian cancer and endometrial cancer (CA125), prostate cancer (PSA), lung cancer (CYFRA21-1) and pancreatic cancer (CA242), which serve as auxiliary efficacy indicators.  
2) If a subject received a CT/MRI or other radiological examinations within 4 weeks prior to the first dose and has not received any anti-tumor therapy since this tumor assessment, and at the investigator's discretion, the tumor assessment can be performed according to RECIST v1.1, this examination result can be used as baseline tumor assessment result (repeated examination is not necessary).  
➢ **Biomarker detection:** See Section 4.4.3 for details. ➢ AE: See Section 8 for details.  
➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.  
➢ **Reviewing inclusion/exclusion criteria.**
Subjects who have passed the screening will be enrolled into this trial.  
4.3.2 **Single-dose phase (for dose escalation trial only)**
clinical trial protocol
day 1 (d1)

Specific procedures and assessments are as follows:
➢ **Vital signs:** Body temperature, blood pressure, heart rate and respiration. For D1, it will be measured within 1 h pre-dose and at 10 h (±1 h) post-dose on D1. If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. For D1, it will be measured within 1 h pre-dose and at 10 h (±1 h) post-dose on D1. If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
➢ **Study drug administration:** See Section 5.2 and Section 6.1 for details.  
➢ **PK blood collection:** See Section 4.4.1 for details. ➢ **Blood collection for metabolite identification:** See Section 4.4.2 for details. ➢ AE: See Section 8 for details.  
➢ **DLT evaluation.**
➢ **Concomitant medications**: see Section 6.2 for details. ➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.
clinical trial protocol
day 2 (d2)

Specific procedures and assessments are as follows:
➢ **PK blood collection:** See Section 4.4.1 for details. ➢ **Blood collection for metabolite identification:** See Section 4.4.2 for details. ➢ AE: See Section 8 for details. ➢ **DLT evaluation.** ➢ **Concomitant medications**: see Section 6.2 for details.  
➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.
clinical trial protocol
day 3 (d3)

Specific procedures and assessments are as follows:
➢ **Vital signs:** Body temperature, blood pressure, heart rate and respiration. Follow the visit time window. If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. Follow the visit time window. If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
➢ **PK blood collection:** See Section 4.4.1 for details.  
➢ **Blood collection for metabolite identification:** See Section 4.4.2 for details.  
➢ AE: See Section 8 for details.  
➢ **DLT evaluation.**
➢ **Concomitant medications**: see Section 6.2 for details.  
➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.
clinical trial protocol
day 4 (d4)

Specific procedures and assessments are as follows:
➢ **PK blood collection:** See Section 4.4.1 for details. ➢ **Blood collection for metabolite identification:** See Section 4.4.2 for details. ➢ AE: See Section 8 for details. ➢ **DLT evaluation.**
➢ **Concomitant medications**: see Section 6.2 for details.  
➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.
clinical trial protocol
day 5 (d5)

Specific procedures and assessments are as follows:
➢ **Hematology:** RBC count, WBC count, ABMONO, PLT count, ANC, ABLYMP, basophil count, ABEOS, ABRETIC, neutrophil ratio, Hb, HCT, mean corpuscular volume, and MCHC.  
➢ **Urinalysis:** Potential of hydrogen (pH), specific gravity, urine RBC, urine WBC, urine glucose, urine bilirubin, urine protein, urobilinogen, urine ketone bodies, and urine occult blood.  
➢ **Stool routine (±1 day):** Color, shape, fecal RBC, fecal WBC, fecal occult blood, fecal choline, and fecal bilirubin.  
➢ Blood biochemistry:
1) **Liver function:** AST, ALT, ALP, LDH, GGT, TBIL, direct bilirubin, total bile acids, ALB,
total protein, and GLO.  
2) **Renal function:** Urea/urea nitrogen, creatinine, creatinine clearance, and uric acid.  
3) **Blood lipids:** Total cholesterol, HDL, LDL, and TG.  
4) **Electrolytes**: Potassium, sodium, chloride, phosphorus, magnesium, and calcium. 5) **Heart function:** CK and CKI. 6) **Blood glucose**: GLU.  
➢ **Coagulation:** Prothrombin time, activated partial thromboplastin time, fibrinogen quantification, and international normalized ratio.  
➢ **Vital signs:** Body temperature, blood pressure, heart rate, and respiration. Follow the visit time window. If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. Follow the visit time window. If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
➢ **Physical examination:** Assessments will be performed per organ and system, and a simple physical examination will be performed at this visit, including but not limited to weight, BMI, general condition, skin, and any abnormal signs of concern at the investigator's discretion.  
➢ **ECOG assessment.** ➢ **PK blood collection:** See Section 4.4.1 for details. ➢ **Blood collection for metabolite identification:** See Section 4.4.2 for details. ➢ AE: See Section 8 for details.  
➢ **DLT evaluation.**
➢ **Concomitant medications**: see Section 6.2 for details.  
➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.  
4.3.3 **Multiple-dose phase**
clinical trial protocol
day 1 of cycle 1

Specific procedures and assessments are as follows:
➢ **Vital signs:** Body temperature, blood pressure, heart rate and respiration. For C1D1, it will be measured within 1 h pre-dose and at 10 h (±1 h) post-dose on C1D1. If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. For C1D1, it will be measured within 1 h pre-dose and at 10 h (±1 h) post-dose on C1D1. If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
➢ **Study drug administration:** See Section 5.2 and Section 6.1 for details.  
➢ **Dispensing diary cards and drugs.** ➢ **PK blood collection:** See Section 4.4.1 for details. ➢ AE: See Section 8 for details.  
➢ **DLT evaluation:** For the dose escalation trial only.  
➢ **Concomitant medications**: see Section 6.2 for details. ➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.
clinical trial protocol
day 8 of cycle 1

Specific procedures and assessments are as follows:
➢ **Hematology:** RBC count, WBC count, ABMONO, PLT count, ANC, ABLYMP, basophil count, ABEOS, ABRETIC, neutrophil ratio, Hb, HCT, mean corpuscular volume, and MCHC. Existing laboratory test results within 48 hours are acceptable.  
➢ **Urinalysis:** Potential of hydrogen (pH), specific gravity, urine RBC, urine WBC, urine glucose, urine bilirubin, urine protein, urobilinogen, urine ketone bodies, and urine occult blood. Existing laboratory test results within 48 hours are acceptable.  
➢ **Stool routine:** Color, shape, fecal RBC, fecal WBC, fecal occult blood, fecal choline, and fecal bilirubin. Existing laboratory test results within 48 hours are acceptable.  
➢ **Blood biochemistry:**
1) **Liver function:** AST, ALT, ALP, LDH, GGT, TBIL, direct bilirubin, total bile acids, ALB,
total protein, and GLO.  
2) Renal **function:** Urea/urea nitrogen, creatinine, creatinine clearance, and uric acid. 3) Blood **lipids:** Total cholesterol, HDL, LDL, and TG. 4) **Electrolytes**: Potassium, sodium, chloride, phosphorus, magnesium, and calcium. 5) Heart **function:** CK and CKI. 6) Blood **glucose**: GLU.  
Existing laboratory test results within 48 hours are acceptable.  
➢ **Coagulation:** Prothrombin time, activated partial thromboplastin time, fibrinogen quantification, and international normalized ratio. Existing laboratory test results within 48 hours are acceptable.  
➢ **Vital signs:** Body temperature, blood pressure, heart rate, and respiration. Follow the visit time window. If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. Follow the visit time window. If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
➢ **Physical examination:** Assessments will be performed per organ and system, and a simple physical examination will be performed at this visit, including but not limited to weight, BMI, general condition, skin, and any abnormal signs of concern at the investigator's discretion.  
➢ **Study drug administration:** See Section 5.2 and Section 6.1 for details.  
➢ **PK blood collection:** See Section 4.4.1 for details. ➢ AE: See Section 8 for details. ➢ **DLT evaluation:** For the dose escalation trial only. ➢ **Concomitant medications**: see Section 6.2 for details. ➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.
clinical trial protocol
day 15 of cycle 1

Specific procedures and assessments are as follows:
➢ **Hematology:** RBC count, WBC count, ABMONO, PLT count, ANC, ABLYMP, basophil count, ABEOS, ABRETIC, neutrophil ratio, Hb, HCT, mean corpuscular volume, and MCHC. Existing laboratory test results within 48 hours are acceptable.  
➢ **Urinalysis:** Potential of hydrogen (pH), specific gravity, urine RBC, urine WBC, urine glucose, urine bilirubin, urine protein, urobilinogen, urine ketone bodies, and urine occult blood. Existing laboratory test results within 48 hours are acceptable.  
➢ **Stool routine:** Color, shape, fecal RBC, fecal WBC, fecal occult blood, fecal choline, and fecal bilirubin. Existing laboratory test results within 48 hours are acceptable.
clinical trial protocol
blood biochemistry

1) **Liver function:** AST, ALT, ALP, LDH, GGT, TBIL, direct bilirubin, total bile acids, ALB,
total protein, and GLO.  
2) Renal **function:** Urea/urea nitrogen, creatinine, creatinine clearance, and uric acid.  
3) Blood **lipids:** Total cholesterol, HDL, LDL, and TG.  
4) **Electrolytes**: Potassium, sodium, chloride, phosphorus, magnesium, and calcium.  
5) Heart **function:** CK and CKI. 6) Blood **glucose**: GLU.  
Existing laboratory test results within 48 hours are acceptable.  
➢ **Coagulation:** Prothrombin time, activated partial thromboplastin time, fibrinogen quantification, and international normalized ratio. Existing laboratory test results within 48 hours are acceptable.  
➢ **Vital signs:** Body temperature, blood pressure, heart rate, and respiration. Follow the visit time window. If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. Follow the visit time window. If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
➢ **Physical examination:** Assessments will be performed per organ and system, and a simple physical examination will be performed at this visit, including but not limited to weight, BMI, general condition, skin, and any abnormal signs of concern at the investigator's discretion.  
➢ **Study drug administration:** See Section 5.2 and Section 6.1 for details.  
➢ **Biomarker detection:** See Section 4.4.3 for details.  
➢ **PK blood collection:** See Section 4.4.1 for details.  
➢ AE: See Section 8 for details.  
➢ **DLT evaluation:** For the dose escalation trial only.  
➢ **Concomitant medications**: see Section 6.2 for details.
clinical trial protocol
inpatient nutrition assessment (nrs-2002) assessed

Specific procedures and assessments are as follows:
➢ **Hematology:** RBC count, WBC count, ABMONO, PLT count, ANC, ABLYMP, basophil count, ABEOS, ABRETIC, neutrophil ratio, Hb, HCT, mean corpuscular volume, and MCHC. Existing laboratory test results within 48 hours are acceptable.  
➢ **Urinalysis:** Potential of hydrogen (pH), specific gravity, urine RBC, urine WBC, urine glucose, urine bilirubin, urine protein, urobilinogen, urine ketone bodies, and urine occult blood. Existing laboratory test results within 48 hours are acceptable.  
➢ **Stool routine:** Color, shape, fecal RBC, fecal WBC, fecal occult blood, fecal choline, and fecal bilirubin. Existing laboratory test results within 48 hours are acceptable.
clinical trial protocol
blood biochemistry

1) **Liver function:** AST, ALT, ALP, LDH, GGT, TBIL, direct bilirubin, total bile acids, ALB,
total protein, and GLO.  
2) Renal **function:** Urea/urea nitrogen, creatinine, creatinine clearance, and uric acid. 3) Blood **lipids:** Total cholesterol, HDL, LDL, and TG. 4) **Electrolytes**: Potassium, sodium, chloride, phosphorus, magnesium, and calcium. 5) Heart **function:** CK and CKI.
clinical trial protocol
6) blood glucose glu.

Existing laboratory test results within 48 hours are acceptable.  
➢ **Coagulation:** Prothrombin time, activated partial thromboplastin time, fibrinogen quantification, and international normalized ratio. Existing laboratory test results within 48 hours are acceptable.  
➢ **Vital signs:** Body temperature, blood pressure, heart rate, and respiration. Follow the visit time window. If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. For C1D21, ECG will be performed within 0.5 h pre-dose and at 2 h (±15 min), 4 h (±15 min), 6 h (±20 min), 8 h (±30 min), and 24 h (±1 h, pre-dose on C2D1) post-pose on C1D21. If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
➢ **Physical examination:** Assessments will be performed per organ and system, and a simple physical examination will be performed at this visit, including but not limited to weight, BMI, general condition, skin, and any abnormal signs of concern at the investigator's discretion.  
➢ **ECOG assessment.**
➢ **Pregnancy-related tests:** For women of childbearing potential, HCG will be tested. Blood HCG pregnancy test at screening visit should be completed within 7 days prior to the first dose.  
➢ **Echocardiography:** LVEF. During treatment, echocardiography will be performed at the same frequency with tumor assessment, i.e., echocardiography will be performed at the end of the 1st cycle, and the time window is ±1 day after the end of the cycle.  
➢ **Study drug administration:** See Section 5.2 and Section 6.1 for details.  
➢ **Dispensing/collecting diary cards and drugs.**
clinical trial protocol
tumor assessment

1) Imaging tests like CT/MRI and other radiological examinations of chest, upper abdomen, lower abdomen, pelvic cavity and other positions will be performed. If brain metastasis is confirmed at screening, the frequency of brain CT/MRI in the subsequent cycles should be kept consistent with the tumor assessment frequency specified in the study; if it is confirmed that there is no brain metastasis by brain CT/MRI at screening, brain CT/MRI will be performed for confirmation if brain metastasis is suspected by the investigator later. If bone metastasis is confirmed at screening, a bone scan or contrast-enhanced MRI
(for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if progression of the pre-existing bone metastasis or new bone metastasis is suspected by the investigator later; if it is confirmed that there is no bone metastasis at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if bone metastasis is suspected by the investigator later. Tumor assessments will be performed according to RECIST v1.1. Tumor markers: During the corresponding visits for imaging tests, 4 mL of peripheral blood will be collected for the detection of tumor biomarkers, such as liver cancer (AFP, CEA), breast cancer (CA15-3), ovarian cancer and endometrial cancer (CA125), prostate cancer (PSA), lung cancer (CYFRA21-1) and pancreatic cancer (CA242), which serve as auxiliary efficacy indicators.  
2) A tumor assessment will be performed at the end of Cycle 1, for which the time window is the end of the cycle ± 1 day [if a subject's assessment result is complete response (CR), partial response (PR) or stable disease (SD), the subject can continue the treatment and continue to receive tumor assessments once every 2 cycles].  
3) The radiological confirmation examination of CR or PR should be completed 4-8 weeks after the first evaluation of CR or PR.  
➢ **PK blood collection:** See Section 4.4.1 for details.  
➢ AE: See Section 8 for details.  
➢ **DLT evaluation:** For the dose escalation trial only.  
➢ **Concomitant medications**: see Section 6.2 for detials.  
➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.  
Day 1 of Cycle 2 (C2D1; time window for corresponding examination: ± 1 day): Specific procedures and assessments are as follows:
➢ **PK blood collection:** See Section 4.4.1 for details. ➢ AE: See Section 8 for details. ➢ **Concomitant medications**: see Section 6.2 for detials. ➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.  
Starting from Cycle 2 treatment, on Day 21 of each cycle of treatment (CnD21; time **window** for corresponding examinations: ±3 days): Specific procedures and assessments are as follows:
➢ **Hematology:** RBC count, WBC count, ABMONO, PLT count, ANC, ABLYMP, basophil count, ABEOS, ABRETIC, neutrophil ratio, Hb, HCT, mean corpuscular volume, and MCHC. Twice in Cycle 2, e.g., D14 and D21 of the cycle, with a time window of ±3 days; for Cycles 3 to 5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days.  
➢ **Urinalysis:** Potential of hydrogen (pH), specific gravity, urine RBC, urine WBC, urine glucose, urine bilirubin, urine protein, urobilinogen, urine ketone bodies, and urine occult blood. For Cycle 2-5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days.  
➢ **Stool routine:** Color, shape, fecal RBC, fecal WBC, fecal occult blood, fecal choline, and fecal bilirubin. For Cycle 2-5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days.
clinical trial protocol
blood biochemistry

1) **Liver function:** AST, ALT, ALP, LDH, GGT, TBIL, direct bilirubin, total bile acids, ALB,
total protein, and GLO.  
2) Renal **function:** Urea/urea nitrogen, creatinine, creatinine clearance, and uric acid. 3) Blood **lipids:** Total cholesterol, HDL, LDL, and TG.  
4) **Electrolytes**: Potassium, sodium, chloride, phosphorus, magnesium, and calcium.  
5) Heart **function:** CK and CKI.
clinical trial protocol
6) blood glucose glu.

Twice in Cycle 2, e.g., D14 and D21 of the cycle, with a time window of ±3 days; for Cycles 3 to 5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days.  
➢ **Coagulation:** Prothrombin time, activated partial thromboplastin time, fibrinogen quantification, and international normalized ratio. Twice in Cycle 2, e.g., D14 and D21 of the cycle, with a time window of ±3 days; for Cycles 3 to 5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days.  
➢ **Vital signs:** Body temperature, blood pressure, heart rate, and respiration. Performed in accordance with the visit time window (twice in Cycle 2, e.g., D14 and D21 of the cycle, with a time window of ±3 days; for Cycles 3 to 5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days). If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. Performed in accordance with the visit time window (twice in Cycle 2, e.g., D14 and D21 of the cycle, with a time window of ±3 days; for Cycles 3 to 5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days). If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
➢ **Physical examination:** Assessments will be performed per organ and system, and a simple physical examination will be performed at this visit, including but not limited to weight, BMI, general condition, skin, and any abnormal signs of concern at the investigator's discretion. Twice in Cycle 2, e.g., D14 and D21 of the cycle, with a time window of ±3 days; for Cycles 3 to 5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days.  
➢ **ECOG assessment:** For Cycle 2-5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days.  
➢ **Pregnancy-related tests:** For women of childbearing potential, HCG will be tested. Blood HCG pregnancy test at screening visit should be completed within 7 days prior to the first dose. For Cycle 2-5, once at the end of each cycle, with a time window of ±3 days; since Cycle 6, once at the end of every 2 cycles, with a time window of ±3 days.  
➢ **Echocardiography:** LVEF. During treatment, echocardiography will be performed at the same frequency with tumor assessment, i.e., after the end of the 1st cycle, echocardiography will be performed every 2 cycles with a time window of ±7 days from the end of every 2 cycles.  
➢ **Study drug administration:** See Section 5.2 and Section 6.1 for details.
clinical trial protocol
dispensing/collecting diary cards and drugs.

1) Imaging tests like CT/MRI and other radiological examinations of chest, upper abdomen, lower abdomen, pelvic cavity and other positions will be performed. If brain metastasis is confirmed at screening, the frequency of brain CT/MRI in the subsequent cycles should be kept consistent with the tumor assessment frequency specified in the study; if it is confirmed that there is no brain metastasis by brain CT/MRI at screening, brain CT/MRI
will be performed for confirmation if brain metastasis is suspected by the investigator later. If bone metastasis is confirmed at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if progression of the pre-existing bone metastasis or new bone metastasis is suspected by the investigator later; if it is confirmed that there is no bone metastasis at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if bone metastasis is suspected by the investigator later. Tumor assessments will be performed according to RECIST v1.1. Tumor markers: During the corresponding visits for imaging tests, 4 mL of peripheral blood will be collected for the detection of tumor biomarkers, such as liver cancer (AFP, CEA), breast cancer (CA15-3), ovarian cancer and endometrial cancer (CA125), prostate cancer (PSA), lung cancer (CYFRA21-1) and pancreatic cancer (CA242), which serve as auxiliary efficacy indicators.  
2) Tumor assessments will be performed once every 2 cycles after the end of Cycle 1, for which the time window is the end of every 2 cycles ± 7 days [if a subject's assessment result is CR, PR or SD, the subject can continue the treatment and continue to receive tumor assessments once every 2 cycles].  
3) The radiological confirmation examination of CR or PR should be completed 4-8 weeks after the first evaluation of CR or PR.
➢ **Biomarker detection:** See Section 4.4.3 for details. ➢ AE: See Section 8 for details.  
➢ **Concomitant medications**: see Section 6.2 for details. ➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.
clinical trial protocol
4.3.4 end of study treatment

Specific procedures and assessments are as follows:
➢ **Hematology:** RBC count, WBC count, ABMONO, PLT count, ANC, ABLYMP, basophil count, ABEOS, ABRETIC, neutrophil ratio, Hb, HCT, mean corpuscular volume, and MCHC. Existing laboratory test results within the visit time window are acceptable.  
➢ **Urinalysis:** Potential of hydrogen (pH), specific gravity, urine RBC, urine WBC, urine glucose, urine bilirubin, urine protein, urobilinogen, urine ketone bodies, and urine occult blood. Existing laboratory test results within the visit time window are acceptable.  
➢ **Stool routine:** Color, shape, fecal RBC, fecal WBC, fecal occult blood, fecal choline, and fecal bilirubin. Existing laboratory test results within the visit time window are acceptable.
clinical trial protocol
blood biochemistry

1) **Liver function:** AST, ALT, ALP, LDH, GGT, TBIL, direct bilirubin, total bile acids, ALB,
total protein, and GLO.  
2) Renal **function:** Urea/urea nitrogen, creatinine, creatinine clearance, and uric acid. 3) Blood **lipids:** Total cholesterol, HDL, LDL, and TG.  
4) **Electrolytes**: Potassium, sodium, chloride, phosphorus, magnesium, and calcium.  
5) Heart **function:** CK and CKI. 6) Blood **glucose**: GLU.  
Existing laboratory test results within the visit time window are acceptable.  
➢ **Coagulation:** Prothrombin time, activated partial thromboplastin time, fibrinogen quantification, and international normalized ratio. Existing laboratory test results within the visit time window are acceptable.  
➢ **Vital signs:** Body temperature, blood pressure, heart rate, and respiration. Follow the visit time window. If there are corresponding clinical symptoms at other time, vital signs should also be measured, and the data should be recorded.  
➢ **12-lead ECG:** Measurements will be performed after resting in supine position, and the data
(PR, QRS, QT and QTcF) will be recorded. Follow the visit time window. If there are corresponding clinical symptoms at other time, ECG should also be performed, the data should be recorded, and the ECG results should be kept.  
➢ **Physical examination:** Assessments will be performed per organ and system, and a simple physical examination will be performed at this visit, including but not limited to weight, BMI, general condition, skin, and any abnormal signs of concern at the investigator's discretion.
clinical trial protocol
ecog assessment. pregnancy-related tests

1) For women of childbearing potential, HCG will be tested. 2) For men and women ≥60 years of age, a pregnancy-related test is not required.  
➢ **Echocardiography:** LVEF.
clinical trial protocol
collecting diary cards and drugs.

1) Imaging tests like CT/MRI and other radiological examinations of chest, upper abdomen, lower abdomen, pelvic cavity and other positions will be performed. If brain metastasis is confirmed at screening, the frequency of brain CT/MRI in the subsequent cycles should be kept consistent with the tumor assessment frequency specified in the study; if it is confirmed that there is no brain metastasis by brain CT/MRI at screening, brain CT/MRI will be performed for confirmation if brain metastasis is suspected by the investigator later. If bone metastasis is confirmed at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if progression of the pre-existing bone metastasis or new bone metastasis is suspected by the investigator later; if it is confirmed that there is no bone metastasis at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if bone metastasis is suspected by the investigator later. Tumor assessments will be performed according to RECIST v1.1. Tumor markers: During the corresponding visits for imaging tests, 4 mL of peripheral blood will be collected for the detection of tumor biomarkers, such as liver cancer (AFP, CEA), breast cancer (CA15-3), ovarian cancer and endometrial cancer (CA125), prostate cancer (PSA), lung cancer (CYFRA21-1) and pancreatic cancer (CA242), which serve as auxiliary efficacy indicators.  
2) For the EOT, the investigator will determine whether a tumor assessment is required according to the condition. If a tumor assessment has been performed within 2 months prior to EOT, it is not necessary to repeat the tumor assessment at EOT visit.  
3) The radiological confirmation examination of CR or PR should be completed 4-8 weeks after the first evaluation of CR or PR.  
➢ **Biomarker detection:** See Section 4.4.3 for details. ➢ AE: See Section 8 for details.  
➢ **Concomitant medications**: see Section 6.2 for details.  
➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.
clinical trial protocol
4.3.5 follow-up period

Safety visit [28 days (±7 days) after the last dose]: Specific procedures and assessments are as follows:
➢ **Hematology:** RBC count, WBC count, ABMONO, PLT count, ANC, ABLYMP, basophil count, ABEOS, ABRETIC, neutrophil ratio, Hb, HCT, mean corpuscular volume, and MCHC. Existing laboratory test results within the visit time window are acceptable.  
➢ **Urinalysis:** Potential of hydrogen (pH), specific gravity, urine RBC, urine WBC, urine glucose, urine bilirubin, urine protein, urobilinogen, urine ketone bodies, and urine occult blood. Existing laboratory test results within the visit time window are acceptable.  
➢ **Stool routine:** Color, shape, fecal RBC, fecal WBC, fecal occult blood, fecal choline, and fecal bilirubin. Existing laboratory test results within the visit time window are acceptable.
clinical trial protocol
blood biochemistry

1) **Liver function:** AST, ALT, ALP, LDH, GGT, TBIL, direct bilirubin, total bile acids, ALB,
total protein, and GLO.  
2) Renal **function:** Urea/urea nitrogen, creatinine, creatinine clearance, and uric acid. 3) Blood **lipids:** Total cholesterol, HDL, LDL, and TG. 4) **Electrolytes**: Potassium, sodium, chloride, phosphorus, magnesium, and calcium.
clinical trial protocol
5) heart function ck and

Existing laboratory test results within the visit time window are acceptable.  
➢ **Coagulation:** Prothrombin time, activated partial thromboplastin time, fibrinogen quantification, and international normalized ratio. Existing laboratory test results within the visit time window are acceptable.  
➢ **Anti-cancer therapy and survival information after study treatment discontinuation:**
During the follow-up period following study treatment discontinuation, the anti-cancer therapy and survival information of all subjects will be recorded.  
➢ AE: See Section 8 for details. ➢ **Concomitant medications**: see Section 6.2 for details. ➢ **Inpatient nutrition assessment (NRS-2002):** assessed as needed.
clinical trial protocol
tumor assessment

1) Imaging tests like CT/MRI and other radiological examinations of chest, upper abdomen, lower abdomen, pelvic cavity and other positions will be performed. If brain metastasis is confirmed at screening, the frequency of brain CT/MRI in the subsequent cycles should be kept consistent with the tumor assessment frequency specified in the study; if it is confirmed that there is no brain metastasis by brain CT/MRI at screening, brain CT/MRI
will be performed for confirmation if brain metastasis is suspected by the investigator later. If bone metastasis is confirmed at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if progression of the pre-existing bone metastasis or new bone metastasis is suspected by the investigator later; if it is confirmed that there is no bone metastasis at screening, a bone scan or contrast-enhanced MRI (for those allergic to contrast medium, MRI plain scan is acceptable) will be performed for confirmation if bone metastasis is suspected by the investigator later. Tumor assessments will be performed according to RECIST v1.1. Tumor markers: During the corresponding visits for imaging tests, 4 mL of peripheral blood will be collected for the detection of tumor biomarkers, such as liver cancer (AFP, CEA), breast cancer (CA15-3), ovarian cancer and endometrial cancer (CA125), prostate cancer (PSA), lung cancer (CYFRA21-1) and pancreatic cancer (CA242), which serve as auxiliary efficacy indicators.  
2) During the subsequent follow-up visits once every 8 weeks (±7 days) after the last dose, a tumor assessment will be performed for the subjects who are assessed as having no tumor progression in the previous assessment a.  
3) The radiological confirmation examination of CR or PR should be completed 4-8 weeks after the first evaluation of CR or PR.  
➢ **Biomarker detection:** See Section 4.4.3 for details.  
➢ **Anti-cancer therapy and survival information after study treatment discontinuation:**
During the follow-up period following study treatment discontinuation, the anti-cancer therapy and survival information of all subjects will be recorded b.
clinical trial protocol
inpatient nutrition assessment (nrs-2002) assessed

a. Tumor assessments will be performed on subjects whose tumor has not progressed in the last assessment until the subject is lost to follow-up, the subject dies, the subject starts new anti-tumor therapy, the subject requests to withdraw from the trial and refuses to continue follow-up, the research data collection had reached the cutoff date, the study site is early closed, the study is early terminated, or the study ends (whichever occurs first).  
b. During the follow-up period after the end of the study treatment, all subjects will be followed up for the survival period and the tumor treatment status will be recorded until the subject is lost to follow-up, the subject dies, the subject requests to withdraw from the trial and refuses to continue follow-up, the research data collection had reached the cutoff date, the study site is early closed, the study is early terminated, or the study ends (whichever occurs first).
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4.3.6 unscheduled visit

Temporary visit may be conducted when clinically needed. Both the content and results of unscheduled visits should be recorded in the original medical record and eCRF. In addition to the safety test items specified in the protocol, additional safety test items may be measured as necessary. Inpatient nutrition assessment (NRS-2002): assessed as needed.
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4.4 sample collection and testing

According to the *Technical Guidelines for Clinical Pharmacokinetic Studies of Chemical Drugs*, a blank blood sample should be collected before administration. A complete blood drug concentration-time curve should include at least 2-3 sampling points in the absorption phase and at least 3 sampling points near the Cmax; "for multiple administrations, to estimate the time when the drug may reach the steady state concentration, the trough concentration should be measured three times (before administration) to determine the steady state concentration", and there should be at least 3-5 sampling points in the elimination phase. Generally, there are no less than 11-12 sampling points, and there should be a time period of three to five T1/2 or sampling should continue until the plasma concentration is 1/10-1/20 of Cmax. The preliminarily proposed PK blood collection time points are as follows: During the single-dosing period of the dose escalation trial, the PK blood sampling time points are as follows: within 0.5 h (0 h) before single-dosing on D1 and 1 h (±3 min), 2 h (±3 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 10 h (±10 min), 24 h (±1 h; D2), 48 h (±1 h; D3), 72 h (±2 h; D4) and 96 h (±2 h; D5) after dosing. During the multiple-dosing period of the dose escalation trial, the PK blood sampling time points are as follows: within 0.5 h pre-dose on C1D1, within 0.5 h pre-dose on C1D8, within 0.5 h pre-dose on C1D15, within 0.5 h pre-dose and 1 h (±3 min), 2 h (±3 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 10 h (±10 min) and 24 h (±30 min; collected before dosing on C2D1) post-dose on C1D21. During the expansion trial, the PK blood sampling time points are as follows: within 0.5 h pre-dose on C1D1, within 0.5 h pre-dose on C1D8, within 0.5 h pre-dose on C1D15, within 0.5 h pre-dose and 1 h (±3 min), 2 h (±3 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 10 h (±10 min) and 24 h (±30 min; collected before dosing on C2D1) post-dose on C1D21. The PK blood sampling time points of the subsequent study may be adjusted based on the previously obtained clinical trial data of BB102 tablets.  
If there is dose interruption or missed dose(s) of BB102 tablets within 3 days before a PK sample collection time point, the investigator should discuss its impact on the PK sampling schedule with the sponsor and clinical pharmacologist as soon as possible within 24 hours of awareness, thereby determining whether to continue PK blood sampling as planned and how to adjust the PK blood sampling time points. The date and time of each dosing and each blood sampling should be recorded. Three mL of venous blood will be collected each time. The plasma will be divided into 2 tubes: 1 tube for backup and 1 tube for PK detection. The collection, preservation and transportation of PK samples should follow the corresponding national regulations as well as the SOPs and manuals of the responsible facilities (including the laboratory of each study site and the central laboratory). Note: Collected blood samples should be protected from hemolysis as far as possible. Concentration of BB102 (and its main metabolites, if applicable) in the PK samples will be quantitatively measured using the methodologically validated high-performance liquid chromatography- mass spectrometry/ mass spectrometry (HPLC-MS/MS) method. PK sample testing should follow the corresponding national regulations as well as the SOPs and manuals of the testing facility (central laboratory).
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4.4.2 samples for metabolite identification

Blood samples will be collected for identification of metabolites only at a high dose group (e.g., 160 mg QD, 240 mg QD, 320 mg QD or 420 mg) during the single-dosing period of the dose escalation trial. Blood sampling time points: within 0.5 h (0 h) before single-dosing on D1 and 1 h (±3 min), 2 h (±3 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 10 h (±10 min), 24 h (±1 h; D2), 48 h (±1 h; D3), 72 h (±2 h; D4) and 96 h (±2 h; D5) after dosing. For the blood sampling time points where PK samples and metabolite identification samples will be collected at the same time, a total of 4 mL of whole blood will be collected each time. Plasma will be divided into 3 tubes: 1 tube for backup, 1 tube for PK detection, and 1 tube for metabolite identification (the tube should contain ≥0.6 mL plasma). The collection, preservation, transportation, and testing of these samples should follow the corresponding national regulations as well as the SOPs and manuals of the responsible facilities (including the laboratory of each study site and the central laboratory).
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4.4.3 detection of biomarkers 1)

The corresponding biomarkers include but are not limited to the protein expression level, amplification, mRNA level, and activating mutation of FGF19 or FGFR4 in tumor tissue. Subjects' tumor tissue specimens within the past 2 years or fresh tumor tissue specimens can be collected at screening; the specimens can be collected from the primary lesion or metastatic lesions. After enrollment, fresh tumor tissue specimens will be collected as much as possible at EOT visit or disease progression; the specimens can be collected from the primary lesion or metastatic lesions (keeping consistent with the lesion source at screening as much as possible).
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2) detection of biomarkers in

The corresponding biomarkers include but are not limited to blood bile acid precursors (e.g., 7-αhydroxy-4-cholestene-3-one), total bile acids, total cholesterol, TG, and serum FGF19 protein content. Fresh blood samples can be collected at screening, during the treatment period (C1D15 visit, C3D21 visit and C5D21 visit) and at EOT visit, 5 mL at each time point, with no more than 5
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sampling time points.

The collection, preservation, transportation (if applicable) and testing of biomarker testing samples should follow the corresponding national regulations as well as the SOPs and manuals of the responsible facilities (including the laboratory of each study site and the central laboratory).
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4.4.4 other biological samples

Other biological samples include biological samples obtained for hematology, urinalysis, fecal analysis, blood biochemistry, coagulation function, pregnancy-related tests, serum etiological examinations and other examinations. The collection, preservation, transportation (if applicable) and testing of these samples should follow the corresponding national regulations as well as the SOPs and manuals of the responsible facilities (including the laboratory of each study site).
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4.6 early closure of the

Reasons of early closure of the study site/study suspension/early termination of the study include but are not limited to:
The study site has serious non-compliance issues or non-compliance issues that have not been corrected after dissuasion, such as non-compliance with the protocol or the relevant regulations or guidelines for trials.  
Any new drug toxicity is discovered, or the subject experiences unexpected severe impairment
(including nonclinical and clinical manifestations).  
Enrollment and follow-up of subjects has been completed. The protocol is not followed. The drug study plan (e.g., if the sponsor considers continuation of this study is inappropriate for medical, ethical or commercial reason) is changed.  
The enrollment is too slow.  
The quality of clinical data is poor.  
The Ethics Committee, the investigators, and the sponsor have the right to close the study site early, suspend or prematurely terminate part of the clinical trial or the entire clinical trial:
If the Ethics Committee makes the above decision, the investigator should immediately report to the clinical trial institution and the sponsor and provide detailed written explanation.  
If the investigator makes the above decision without consultation with the sponsor, the investigator should immediately report it to the clinical trial institution, the sponsor and Ethics Committee and provide detailed written explanation.  
If the sponsor makes the above decision, the sponsor should notify all relevant investigators, clinical trial institutions, and drug regulatory authorities; the investigator should immediately report to the clinical trial institution and the Ethics Committee and provide detailed written explanation.  
All study materials (except documents that must be retained at the study site) must be returned to the sponsor upon early closure of the study site or early termination of the study. The investigator must store relevant documents until notification of destruction from the sponsor.
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4.7 definition of study data

The cut-off time for data collection of this Phase I study is 8 weeks after the last subject starts the study treatment, unless the entire study is prematurely terminated (see Section 4.6). At the time of study data collection cutoff, if a subject can tolerate the study drug and remains CR/PR/SD and is willing to continue the study drug treatment, the investigator believes that the subject will still clinically benefit from the continued treatment and the investigator confirms that there is no problem in drug supply after discussion with the sponsor, the subject can continue the study drug treatment (i.e., compassionate use), until he/she meets the criteria for study treatment discontinuation or there is a drug supply problem (whichever occurs first). During the compassionate use, drug-related AEs and SAEs will be recorded according to the relevant national regulations, and the SAEs will be reported to the sponsor/CRO safety department. Routine safety monitoring should be continued as needed. The investigator will select and schedule test items at his/her own discretion and should preserve relevant documents in the source files. The sponsor will not routinely collect relative results of these tests. Data collected during compassionate use will not be included in statistical analysis of the study.
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4.8 number of study sites

This trial is planned to be carried out at 3-6 study sites in the United States of America.  
4.9 **Study Duration**
Approximately 24 months.
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5. study medication 5.1 drug

| Table 2 Basic information of BB102 tablets   |                         |
|----------------------------------------------|-------------------------|
| Generic name:                                | BB102 Tablets           |
| Dosage form:                                 | Tablet                  |
| Active ingredients:                          | BB102                   |
| Molecular formula of  active ingredient:     | C26H30N8O4·C6H8O7       |
| Appearance of active  ingredients:           | Off-white powder        |
| CAS number of active  ingredient:            | None                    |
| Molecular weight of  active ingredient:      | 710.70                  |
| Strength:                                    | 10 mg、50 mg            |
| Package specification:                       | 50 tablets/bottle       |
| Shelf life:                                  | 24 months tentatively   |
| Drug source:                                 | Provided by the sponsor |
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5.2 method of administration

1. **Dose levels:** possibly 50 mg QD, 100 mg QD, 160 mg QD, 240 mg QD, 320 mg QD and 420 mg QD (for the dose escalation groups, the escalation doses may be adjusted according to the previously obtained clinical trial data of BB102 tablets, e.g., adding dose groups of 520 mg QD and 600 mg QD).
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2. administration route oral. 3.

➢ For dose groups 1, 2, 3, 4, 5 and 6 in the dose escalation trial, subjects will be fasted overnight for at least 10 hours before dosing on D1 and C1D21 and take BB102 tablets with about 240 mL of water; no drinking is allowed from 1 h pre-dose to 1 h post-dose; and no food is allowed within 2 h post-dose. Subjects will be on a normal diet.  
➢ For dose groups 1, 2, 3, 4, 5 and 6 in the dose escalation trial, subjects will be fasted at least 2 hours before dosing on the other dosing days, and take BB102 tablets with water; no food is allowed within 1 h post-dose. Subjects will be on a normal diet.  
➢ For dose groups A in the dose escalation trial, subjects will be fasted overnight for at least 10 hours before dosing on D1 and C1D21, start eating a low-fat meal at 30 min before dosing on D1 and C1D21 (breakfast), finish the meal within 30 min and take BB102 tablets with about 240 mL of water at 30 min from the start of meal (if the meal takes more than 30 minutes, BB102 tablets should be administered immediately after the meal); no drinking is
allowed from 1 h pre-dose to 1 h post-dose; no food is allowed within 4 h post-dose. Except for the low-fat meal (breakfast) on the specified days, subjects will be on a normal diet.  
| Total calories (kcal)              | 400-500                                              |                                   |
|------------------------------------|------------------------------------------------------|-----------------------------------|
| Fat (g)                            | 11-14                                                |                                   |
| Calories from fat (%)              | 25                                                   |                                   |
| An example of a low-fat breakfast* | -                                                    | Eight ounces milk (1 percent fat) |
| -                                  | One boiled egg                                       |                                   |
| -                                  | One packet flavored instant oatmeal made with  water |                                   |  
*Note: 25% of calories are derived from fat. Substitutions can be made to this meal, if the content, volume, and viscosity are maintained. A registered dietician at the study site should determine the appropriate meal to be consumed, based on the fat and calorie requirements assigned to the patient for that treatment day.  
The start/stop time of meal consumption, and estimated % of test meal consumed (based on fat and caloric content), must be listed in the meal record eCRF for patients allocated in exploratory food effect group.  
➢ For dose group A in the dose escalation trial, subjects will take BB102 tablets with water within 30 minutes following the meal on the other dosing days; no food is allowed within 1 h post-dose. Subjects will be on a normal diet.  
➢ In the expansion trial, subjects will be fasted for at least 2 hours before dosing and take BB102 tablets with water; no food is allowed within 1 h post-dose. Subjects will be on a normal diet. Note: The administration method of the expansion trial may be adjusted according to the previously obtained food effect evaluation results of BB102 tablets.
4. **Dosing frequency and cycles:** once daily in 21-day cycles (the dosing frequency and cycle setting may be adjusted according to the previously obtained clinical trial data of BB102 tablets).
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note

Study doctors and nurses are required to instruct subjects to administer the drug as prescribed above.  
For each subject, the time of administration every day should be basically the same.
On the administration day with PK blood collection, the date, time and dosage of each administration of each subject must be truthfully recorded in the eCRF by the investigator or a person authorized by the investigator.  
On the day of administration without PK blood collection, the date, time and dosage of each administration of each subject must be truthfully recorded by the subject in the "Subject Diary Card" and reported to the investigator.
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5.4 drug packaging and labeling

The sponsor and CRO will design the label for all investigational products, package and label them according to *Good Clinical Practice* (GCP) and applicable national regulations. The label of the investigational product should contain the following information: protocol number, sponsor information, "for clinical trial use only", name, dosage form, strength, method of administration, storage conditions, product batch number, expiry date, screening number and cycle number of the investigational drugs used in the clinical trial. Backup medicines should be prepared and used only when the original medicines supposed to be used are lost, soiled or otherwise unsuitable for use.
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5.5 drug management

The investigator and clinical trial institution are responsible for the management of investigational products provided by the sponsor. Records of investigational product management should include date, quantity, batch number/serial number, shelf life, distribution code and signature, etc. An investigational product management system should be established to meet the following requirements:  
1) A special person (e.g., a qualified pharmacist) should be responsible for receiving the investigational products provided by the sponsor (the drug receipt form should be signed in duplicate upon receipt of the drug, one for the clinical study institution and one for the sponsor);
2) A designated person is responsible for the reasonable and safe storage of investigational
products, and should ensure that the storage conditions meet the requirements;  
3) Investigational products can only be prescribed by the investigator or a study doctor authorized by the investigator; 4) The investigational products can only be distributed to the subjects or administering nurses according to the trial protocol, and the dosage and administration should follow the trial protocol; 5) If there are problems with the quality and appearance of the investigational products, they shall not be distributed. Instead, the sponsor should be promptly contacted; 6) The investigational products shall not be handed over to any non-trial participant;
7) The distribution and recovery of investigational products need to be fully recorded;  
8) Subjects should return the remaining drugs of BB102 tablets and empty packages of used drugs to the investigator; 9) The investigator should keep the remaining drugs of BB102 tablets and empty packages of used drugs, and keep records of the quantity and dosage of the investigational products used by each subject for monitoring by the monitor;
10) After the drugs are counted during the visit, medication errors, overdose, and drug loss should be recorded in the source medical record and eCRF;
11) Clinical research associate should be responsible for monitoring the supply, use and storage of the investigational drugs and handling process of the remaining drug; 12) After counting by the monitor, the remaining drugs of BB102 tablets and empty packages of used drugs will be recovered by the sponsor (both parties should sign the drug recovery form);  
13) At the end of the trial, the used and residual quantity of the investigational product should be consistent with the quantity provided by the sponsor. Any difference should be recorded and the cause of difference should be specified.
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6. treatment of subjects 6.1

All subjects in the phase I trial will receive continuous administration until they meet the criteria for discontinuation of study treatment.
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6.1.2 dose interruption resumption adjustment

There is currently no data on BB102 tablets in humans, and its ADR is unclear. According to nonclinical toxicology data and ADRs that have been reported for similar drugs, for each single subject, the following methods of dose interruption, resumption, adjustment, and permanent discontinuation are tentatively determined. In the dose escalation trial, dose interruption, resumption and permanent discontinuation during the DLT observation period:
➢ No dose adjustment is allowed in the DLT observation period, but the doses may be interrupted, resumed and permanently discontinued.  
➢ If several toxicities occur at the same time, dose interruption, resumption and permanent discontinuation should be carried out according to the most serious toxicity.  
(1) During the DLT observation period, if the subject develops DLT, the doses should be interrupted, and supportive treatment should be given as needed. The doses can be continued when the dosage has been administered before dose interruption is more than 75% of the scheduled dose, and the subject recovers to grade ≤1 or baseline (or, recovers to grade ≤2 and the investigator believes that there is no safety risk).  
(2) If the subject develops DLT again, the doses should be permanently discontinued, and unscheduled safety follow-up should be arranged until the toxicity is resolved or stabilized.  
(3) If the subject has other non-DLT toxicities, dose interruption needs to be determined according to the investigator's medical assessment, and supportive treatment will be provided as needed. Dose interruption, resumption, adjustment and permanent discontinuation in post-DLT observation period of dose escalation trial and during the dosing period in the expansion trial:
➢ If the AE is attributable to BB102 tablets according to the investigator's judgment, dose interruption, resumption, adjustment and permanent discontinuation will be performed according to the following table. If there is any other situation not described in the table below, the sponsor and investigator will decide whether to interrupt, resume, adjust, or permanently discontinue the dose after a comprehensive assessment of the benefits and risks.  
➢ Subjects can be given appropriate supportive treatment to relieve symptoms and signs of toxic reactions.  
➢ Dose interruption, resumption, adjustment and permanent discontinuation should be perfomed according to the most serious toxic reaction when several toxic reactions occur simultaneously.  
➢ Once the dose is decreased, up-titration to the previous level is not allowed. ➢ A maximum of 2 dose interruptions is allowed for each subject, and each interruption shall not exceed 14 days. If a 3rd dose interruption is required, or a dose interruption is required for >14 days, permanent discontinuation is required for the subject unless it is considered that the continuation of BB102 tablets treatment at an appropriate dose is in the best interest of the patient after the sponsor and the investigator comprehensively evaluate the benefits and risks.  
➢ Rules for dose interruption, resumption, adjustment and permanent discontinuation are shown in the table below.  
| in the table below.                  |                                                                                                                                                                                                                                                                                                                                                                                                                                 |            |
|--------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|
| Hematologic toxicity a               | Rules for dose interruption, resumption,                                                                                                                                                                                                                                                                                                                                                                                        | adjustment |
| and permanent discontinuation b      |                                                                                                                                                                                                                                                                                                                                                                                                                                 |            |
| Neutrophil count decreased Grade 1-2 | Continue the study treatment at the original dose level. Administration interruption until the toxicity is resolved to  grade ≤2. ➢ Resume the study treatment at the original dose level if  the toxicity is resolved within ≤7 days. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within 7-14 days. ➢ Discontinue permanently if the toxicity is resolved  within >14 days. |            |
| Grade 3                              | Administration interruption until the toxicity is resolved to  grade ≤2. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within ≤7 days. ➢ Discontinue permanently if the toxicity is resolved  within >7 days.                                                                                                                                                                  |            |
| Febrile neutropenia Grade 4          | Administration interruption until the toxicity is resolved. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within ≤14 days. ➢ Discontinue permanently if the toxicity is resolved  within >14 days.                                                                                                                                                                             |            |
| Grade 3                              |                                                                                                                                                                                                                                                                                                                                                                                                                                 |            |  
| Grade 4                              | Discontinue permanently.                                                                                                                                                                                                                                                                                                                                                                                                        |
|--------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Platelet count decreased Grade 1-2   | Continue the study treatment at the original dose level. Administration interruption until the toxicity is resolved to  grade ≤1. ➢ Resume the study treatment at the original dose level if  the toxicity is resolved within ≤7 days. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within 7-14 days. ➢ Discontinue permanently if the toxicity is resolved  within >14 days. |
| Grade 3                              | Administration interruption until the toxicity is resolved to  grade ≤1. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within ≤7 days. ➢ Discontinue permanently if the toxicity is resolved  within >7 days.                                                                                                                                                                  |
| Anemia Grade 1-2                     | Continue the study treatment at the original dose level.                                                                                                                                                                                                                                                                                                                                                                        |
| Grade 4                              | Administration interruption until the toxicity is resolved to  grade ≤2. ➢ Resume the study treatment at the original dose level if  the toxicity is resolved within ≤7 days. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within 7-14 days. ➢ Discontinue permanently if the toxicity is resolved  within >14 days.                                                          |
| Grade 3                              | Administration interruption until the toxicity is resolved to  grade ≤2. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within ≤7 days. ➢ Discontinue permanently if the toxicity is resolved within >7 days.                                                                                                                                                                   |
| Other hematologic toxicity Grade 1-2 | Continue the study treatment at the original dose level.                                                                                                                                                                                                                                                                                                                                                                        |
| Grade 4 Grade 3                      | Administration interruption until the toxicity is resolved to  grade ≤2.                                                                                                                                                                                                                                                                                                                                                        |  
| Resume the study treatment at the original dose level after  the toxicity is resolved to grade ≤2. Administration interruption until the toxicity is resolved to  grade ≤2. Resume the study treatment at the original dose level after  the toxicity is resolved to grade ≤2 (the sponsor and  investigator will decide whether to continue the  administration after a comprehensive assessment of the  benefits and risks).   |                                                                                                                                                                                                                                                                                                                                                                      |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Abnormal grade 4 laboratory test  results that are not life-threatening  judged by the investigator                                                                                                                                                                                                                                                                                                                              | Administration interruption until the toxicity is resolved to  grade ≤2. Continue the study treatment at the dose reduced by one  level c after the toxicity is resolved to grade ≤2.                                                                                                                                                                                |
| Grade 4 Nonhematologic toxicity a                                                                                                                                                                                                                                                                                                                                                                                                | Rules for dose interruption, resumptionadjustment and  permanent discontinuation b                                                                                                                                                                                                                                                                                   |
| Creatinine increased Grade 1                                                                                                                                                                                                                                                                                                                                                                                                     | Continue the study treatment at the original dose level. Administration interruption until the toxicity is resolved to  baseline. ➢ Resume the study treatment at the original dose level if  the toxicity is resolved within ≤7 days. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within >7 days.                |
| Grade 3-4                                                                                                                                                                                                                                                                                                                                                                                                                        | Discontinue permanently.                                                                                                                                                                                                                                                                                                                                             |
| Blood bilirubin increased Grade 1                                                                                                                                                                                                                                                                                                                                                                                                | Continue the study treatment at the original dose level.                                                                                                                                                                                                                                                                                                             |
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                          | Administration interruption until the toxicity is resolved to  baseline. ➢ Resume the study treatment at the original dose level if  the toxicity is resolved within ≤7 days. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within >7 days. ➢ Discontinue permanently if the toxicity is resolved  within >14 days. |
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                          | Administration interruption until the toxicity is resolved to  baseline. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within ≤7 days.                                                                                                                                                                              |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                      |  
| ➢                                                                                                                                                                                                                                                                                                                                                                                                                             | Discontinue permanently if the toxicity is resolved within >7 days. Note: Continue the study treatment at  the dose reduced by one level c at the discretion of the  investigator if the grade 3 increase in blood bilirubin is  only due to the increase in indirect bilirubin  (unconjugated bilirubin), and hemolytic factors (e.g.,  peripheral blood smear examination and haptoglobin  assay) have been excluded according to the guidelines  of each study center.   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Discontinue permanently. Note: Continue the study treatment at the dose reduced by  one level c at the discretion of the investigator if the grade  4 increase in blood bilirubin is only due to the increase in  indirect bilirubin (unconjugated bilirubin), and hemolytic  factors (e.g., peripheral blood smear examination and  haptoglobin assay) have been excluded according to the  guidelines of each study center. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| AST or ALT increased Grade 1-2                                                                                                                                                                                                                                                                                                                                                                                                | Continue the study treatment at the original dose level.                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                       | Administration interruption until the toxicity is resolved to  grade ≤2 (liver cancer or liver metastases) or grade ≤1. ➢ Resume the study treatment at the original dose level if  the toxicity is resolved within ≤7 days. ➢ Continue the study treatment at the dose reduced by  one level c if the toxicity is resolved within 7-14 days. ➢ Discontinue permanently if the toxicity is resolved  within >14 days.                                                       |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                       | Discontinue permanently.                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Other nonhematologic toxicity Grade 1-2                                                                                                                                                                                                                                                                                                                                                                                       | Continue the study treatment at the original dose level.                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Grade 3 toxicities with no safety  risk at the discretion of the  investigator, such as grade 3  nausea, vomiting, diarrhea,  asthenia, constipation, loss of  appetite, mucositis, GGT  increased and ALP increased. Grade 3                                                                                                                                                                                                 | Administration interruption until the toxicity is resolved to  grade ≤2. Resume the study treatment at the original dose level after  the toxicity is resolved to grade ≤2.                                                                                                                                                                                                                                                                                                 |  
| Grade 3 Note: Toxicities with no safety  risk at the discretion of the  investigator are excepted, such as  grade 3 nausea, vomiting,  diarrhea, asthenia, constipation, loss of appetite, mucositis, GGT  increased and ALP increased.                                                               | Administration interruption until the toxicity is resolved to  grade ≤2 or grade ≤1. Resume the study treatment at the dose reduced by one  level c after the toxicity is resolved to grade 2 (only when  the investigator believes resuming the study treatment  poses no safety risk to the subject) or grade ≤1.  Administration interruption until the toxicity is resolved to  grade ≤2 or grade ≤1. Resume the study treatment at the dose reduced by one  level c after the toxicity is resolved to grade 2 (only when  the investigator believes resuming the study treatment  poses no safety risk to the subject) or grade ≤1 (the sponsor  and investigator will decide whether to continue the  administration after a comprehensive assessment of the  benefits and risks).   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 4 Toxicities with no safety risk at  the discretion of the investigator are excepted, such as grade 4 GGT increased and ALP increased. Abnormal grade 4 laboratory test  results that are not life-threatening  judged by the investigator (such as  grade 4 GGT increased and ALP  increased). | Discontinue permanently.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Abbreviations: ALP = alkaline phosphatase; DLT = dose-limiting toxicity; GGT = γ-glutamyltransferase. Note: a. Applicable to all hematologic toxicities (if a hematologic toxicity is related to other non-hematologic                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |  
Note: a. Applicable to all hematologic toxicities (if a hematologic toxicity is related to other non-hematologic clinical events, refer to the rules for dose interruption, resumption and adjustment of non-hematologic toxicities). b: The rules may be modified based on the previously obtained clinical trial data of BB102 tablets.  
c. Available dose levels of BB102 tablets include 50 mg QD, 100 mg QD, 160 mg QD, 240 mg QD, 320 mg QD
and 420 mg QD. If dose reduction is required at the starting dose level, the subject should discontinue the treatment permanently.
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6.1.3 medication error and overdose

Medication error is defined as an unexpected deviation in the administration of the investigational product, such as a wrong dose (e.g., overdose), wrong time of administration, wrong route of administration, wrong medication, and use of expired/contaminated/deteriorated study drug. Overdose is defined as the actual dose of the investigational product administered being greater than the planned dose. Any medication error should be recorded as a protocol deviation and recorded in detail in the source medical record and eCRF. If a medication error occurs, regardless of whether it leads to the occurrence of an AE/SAE, the investigator should fill out the "Overdose Report Form" within 24 hours, quickly report it to the sponsor/CRO safety department, and take measures as appropriate, such as delaying subsequent administration and strengthening the monitoring of subjects. If a medication error leads to the occurrence of an AE/SAE, the investigator should give symptomatic treatment according to the situation of the AE/SAE, and report it as an AE or SAE.
clinical trial protocol
6.1.4 treatment of missed doses

On the administration day with PK blood collection, the nurse is responsible for supervision to ensure that the subjects take the medicine on time. On the day of administration without PK blood collection, subjects can take the drug home and take it by themselves. If any dose of BB102 tablets is missed or suspected to be missed, please refer to the following treatment methods:
1) If it is not possible to confirm whether the drug has been taken, it will be deemed that the drug has been taken, and no more additional dose will be taken this time.  
2) When a missed dose is found ≥ half of the dosing interval from the next planned dose (for example, in the case of QD administration, half of 24 hours is 12 hours), the drug will be taken when the missed dose is found.  
3) When a missed dose is found < half of the dosing interval from the next planned dose (for example, in the case of QD administration, half of 24 hours is 12 hours), the drug will not be taken this time, and the prescribed dose will be taken at the time of the next planned dose.  
4) If vomiting occurs after administration, the drug will not be taken this time, and the prescribed dose will be taken at the time of the next planned dose.  
On the day of administration without PK blood collection, the missed doses, the time of missed doses, supplementary doses, and vomiting must be truthfully recorded in the "Subject's Diary Card" and reported to the investigator.
clinical trial protocol
6.2 concomitant medications

Concomitant medications include any medications other than the study drug (including prescription drugs, over-the-counter drugs, natural extracts, nutritional supplements and traditional Chinese medicines) used by subjects from the start of first dose to 28 days after the last dose of study treatment. Note: Medications used by subjects at screening will be recorded as medication history. (1) For the dose escalation trial and expansion trial, the following drugs/therapies will be allowed during the treatment period:
➢ Bisphosphonates for treating bone metastasis. Note: Bisphosphonate therapy should be administered according to the local medical practice.  
➢ Palliative radiotherapy for relieving pain caused by bone lesion, on the condition that this lesion has existed at the time of enrollment and the investigator clarifies the requirement of palliative radiotherapy does not represent disease progression. Note: As there is currently a lack of data on the interaction between BB102 tablets and radiotherapy, BB102 tablets therapy should be interrupted at 1 day before palliative radiotherapy and throughout the radiotherapy period and be resumed after the acute radiotoxicity recovers to baseline level. Note: Palliative radiotherapy is not allowed during the DLT observation period; if the study drug dose received by a subject during the DLT observation period is less than 75% of the scheduled dose due to use of palliative therapy and no DLT occurs, the corresponding dose group needs one more subject for replacement.  
➢ Therapeutic drugs used for AE (dose escalation trial), such as choleretics, but only the nonprohibited medications can be used.  
➢ Preventive drugs and therapeutic drugs used for AE (expansion trial), such as choleretics, but only the non-prohibited medications can be used.  
(2) In the dose escalation trial and expansion trial, the following drugs/therapies will be prohibited during the treatment period:
➢ Anti-tumor therapies rather than the study drug (including but not limited to chemotherapy, radiotherapy, immunotherapy, anti-tumor biotherapy, etc.), including state-approved Chinese traditional patent drugs with an anti-tumor effect.  
➢ Adjuvants (e.g., preventive leukocyte increasing drugs, antiemetics, etc.) related to anti-tumor therapy (for dose escalation trial only).  
➢ Strong CYP3A4 inhibitors, strong CYP3A4 inducers, strong CYP3A5 inhibitors, strong CYP3A5 inducers, sensitive CYP3A4 substrates with a narrow therapeutic index, and sensitive CYP2B6 substrates with a narrow therapeutic index (Appendix IV).  
(3) In the dose escalation trial and expansion trial, the following drugs/therapies can be **used** with **cautious during the treatment period:**
➢ Moderate or weak CYP3A4/5 inhibitors and inducers.  
➢ BCRP substrates, P-gp substrates, OAT1 substrates, OAT3 substrates, OATP1B3 substrates, MATE1 substrates, and MATE2-K substrates with a narrow therapeutic index (Appendix V).  
➢ Strong BCRP inhibitors and strong P-gp inhibitors (Appendix V).  
➢ Drugs which are known to or may prolong QT interval or induce tip torsion ventricular tachycardia (Appendix VI).  
➢ Given that FGFR4 inhibitor can increase CYP7A1 expression, try not to use drugs that can increase CYP7A1 expression or enzyme activity (e.g., atorvastatin, troglitazone); try not to
use cholesterol (CYP7A1 substrates)-containing drugs.
clinical trial protocol
(4) prevention and management of

The actual ADR treatment measures will be taken by the investigator according to the actual situation of the subjects in combination with clinical practice and relevant guidelines. The following suggestions are only for reference. For common ADRs in the dose escalation trial, prophylaxis can be given in advance during the expansion trial.  
➢ Diarrhea: Among the adverse effects of FGFR inhibitor, diarrhea's incidence is 15%-60%,
which may be related to preventing the binding of FGF19 and FGFR4. The homeostasis of bile acids will be regulated after FGF19 binding with FGFR4, while bile acids have effects on colonic mucosal permeability. It is recommended to continue the study treatment at the original dose level, and loperamide, probiotics, and smecta (montmorillonite powder) should be given to treat ADR at the same time when drug-related grade 1-2 diarrhea occurs during the clinical trial. If grade 3 diarrhea occurs, it is recommended to interrupt the study treatment, and loperamide, probiotics, and smecta (montmorillonite powder) should be given to treat ADR at the same time (codeine and prophylactic antibiotics may be used if necessary), the addition of somatostatin may be considered in severe conditions. If grade 4 diarrhea occurs, it is recommended to discontinue the study treatment permanently, at the same time, the above symptomatic treatment should be given.  
➢ Asthenia: FGFR4 has the function of regulating the differentiation of muscle cells and tissue repair. If asthenia occurs in the trial, it is considered to be related to the inhibition of the physiological function of FGFR4. It is recommended to continue the study treatment at the original dose level, and have more rest at the same time when drug-related grade 1-2 asthenia occurs during the clinical trial. If grade 3 asthenia occurs, it is recommended to discontinue the study treatment permanently and have more rest at the same time.  
➢ Nausea/vomiting: They are not caused by FGFR4 physiological mechanism and can be considered as the gastrointestinal irritation of the investigational drug. It is recommended to continue the study treatment at the original dose level, and metoclopramide and so on should be given to treat ADR at the same time when drug-related grade 1-2 nausea/vomiting occurs during the clinical trial. If grade 3 nausea/vomiting occurs, it is recommended to interrupt the study treatment, and metoclopramide and so on should be given to treat ADR at the same time. If grade 4 nausea/vomiting occurs, it is recommended to discontinue the study treatment permanently, and the above symptomatic treatment should be given at the same time.  
➢ Fever: Generally, it may be the non-inflammatory fever caused by the death or rupture of cancer cells. It is recommended to continue the study treatment at the original dose level, at the same time, strengthen body temperature monitoring, and perform physical cooling, ice compress and drink warm water if necessary when drug-related grade 1 fever occurs during the clinical trial. If grade 2 fever occurs, it is recommended to continue the study treatment at the original dose level, and cooling medications (e.g., dexamethasone, loratadine, etc.) should be given to treat ADR at the same time. If grade 3 fever occurs, it is recommended to interrupt the study treatment and the above symptomatic treatment should be given at the same time. If grade 4 fever occurs, it is recommended to discontinue the study treatment permanently, and the above symptomatic treatment should be given at the same time.  
➢ Hepatotoxicity: It is considered to be caused by damage to liver cells or functional overload.  
It is recommended to continue the study treatment at the original dose level, and hepatoprotective medications [e.g., Chinese traditional patent drug, polyene phosphatidylcholine, reduced glutathione, magnesium isoglycyrrhizinate, simetai (adenosylmethionine butanedisulfonate enteric-coated tablet)] should be given for symptomatic treatment at the same time when drug-related grade 1-2 hepatotoxicity occurs during the clinical trial. If grade 3 hepatotoxicity occurs, it is recommended to interrupt the study treatment and the above symptomatic treatment should be given at the same time. If grade 4 hepatotoxicity occurs, it is recommended to discontinue the study treatment permanently, and the above symptomatic treatment should be given at the same time.  
Any prescription drugs, over-the-counter drugs, natural extracts, nutritional supplements, traditional Chinese medicines, herbal medicines and vitamins should be reviewed and approved by the investigator. All information on concomitant medications should be recorded in the subjects' medical records and reported on the eCRF.
clinical trial protocol
6.3 compliance of subjects

The investigator should emphasize the importance of compliance to the subjects during the process of informed consent. During the process of the trial, if a subject's compliance is poor, the investigator should find the cause and actively take corresponding measures (e.g., emphasizing the importance of protocol compliance to the subject), and completely record the related noncompliance, cause and measures taken. The investigator should timely and accurately collect and record the planned dose, actual dose, and date of administration of each subject. In principle, the actual dose should be consistent with the planned dose. The investigator should judge the study treatment compliance according to the medication details. Compliance = actual dose/planned dose × 100%. Subjects taking medication within the range of 80%-120% will be considered to have good treatment compliance.
clinical trial protocol
7. study endpoints 7.1 dose

**Safety and tolerability of BB102 tablets (fasted or fed):** Incidences of AEs and SAEs; abnormalities or changes in laboratory tests, vital signs, ECG, physical examination and ECOG score.  
**DLT of BB102 tablets (fasted or fed):** Classification, severity and frequency of DLT.