Surufatinib in Advanced Hepatocellular Carcinoma Based on Single-cell Sequencing of Tumor Samples

Inclusion Criteria:

• Ages: 18-75 Years（concluding 18 and 75 Years）;
• Radiologically, histologically or cytologically confirmed hepatocellular carcinoma (HCC) with punctable lesions;
• Barcelona Clinic Liver Cancer stage Category B or C
• ECOG PS 0-1, there was no deterioration within 7 days;
• Liver function status Child-Pugh Class A or B (score≤7)
• Has life expectancy of greater than 12 months；
• HCC patients who received first-line standard chemotherapy (systemic chemotherapy withsingle or combination drugs such as oxaliplatin) and/or molecular targeted therapiessuch as sorafenib that failed or were not tolerated;
• Have measurable lesions (according to RECIST 1.1);
• The main organ functions meet the following criteria: (without blood transfusion orany blood component or cell growth factor within 14 days prior to enrollment):Absolute Neutrophil Count (ANC)≥1.5×109/L Platelet Count of ≥100×109/L；Hemoglobin≥90g/L； Total Bilirubin (TBIL)≤1.5 x ULN； ALB≥29 g/L； ALT、AST and ALP≤5 xULN； Creatinine（Cr）≤1.5×ULN (or creatinine clearance (CCr)≥ 60mL/min); (Only one ofalbumin and bilirubin in child-Pugh score can be 2 points)
• Male or females patients with reproductive potential must agree to use an effectivecontraceptive method, for example, double-barrier device, condom, oral or injectedbirth control medication or intrauterine device, during the study and within 90 daysafter study treatment discontinuation. All female patients are considered to befertile, unless the patient had natural menopause or artificial menopause orsterilization (such as hysterectomy, bilateral oophorectomy or ovarian irradiation).
• Good compliance and follow-up

Exclusion Criteria:

• Hepatobiliary duct cell carcinoma and mixed cell carcinoma and fibrolaminar cellcarcinoma；
• Patients who intend to undergo liver transplantation (except those who have previouslyundergone liver transplantation) ;
• Patients who have previously received surufatinib；
• A history of other malignancies within 5 years prior to inclusion, except for cervicalcarcinoma in situ, basal or squamous cell skin cancer, localized prostate cancertreated with radical surgery, and ductal carcinoma in situ treated with radicalsurgery;
• Received investigational treatments in other clinical studies within 4 weeks prior toenrollment;
• Use of approved systematic anti-tumor therapy within 4 weeks prior to the first dose,including chemotherapy, biotherapy, targeted therapy (the washout period of smallmolecular targeted drugs lasts 2 weeks or 5 half-lives, whichever is shorter), hormonetherapy, treatments with traditional Chinese medicine (for patients receivingtreatments with traditional Chinese medicine with clear anti-tumor indications, foranti-tumor indications clearly specified in the package insert, one-week washoutperiod prior to the first dose is acceptable), etc;
• Received any surgical or invasive treatment or operation (except intravenouscatheterization, abdominal puncture and drainage, etc.) within 4 weeks beforeenrollment;
• International normalized ratio(INR) >1.5 or activated partial thromboplastintime(APTT) >1.5×ULN;
• Presence of clinically significant electrolyte abnormality judged by the investigator;
• Hypertension that is not controlled by the drug, and is defined as: SBP ≥140 mmHgand/or DBP ≥90 mmHg；
• With any diseases or conditions prior to enrollment that affected drug absorption, orpatients could not take drugs orally;
• Drugs containing St John's wort taken within 3 weeks prior to the first studytreatment, or other strong inducers with CYP3A4 or strong inhibitors taken within twoweeks prior to the first study treatment;
• Have a gastrointestinal disease or condition that investigators suspect may affectdrug absorption, including, but not limited to, active gastric and duodenal ulcers,ulcerative colitis and other digestive disease, gastrointestinal tumor with activebleeding, or other gastrointestinal conditions that may cause bleeding or perforation,according to the investigator's judgement；
• Patients with evidence or history of obvious bleeding tendency within 3 months beforeenrollment (>30 ml within 3 months, appeared hematemesis, black dung, hematochezia )or Hemoptysis (>5 mL of fresh blood within 4 weeks) or a thromboembolic event (including stroke and/or transient ischemic attacks) within 12 months;
• Have clinically significant cardiovascular disease, including but not limited to,acute myocardial infarction; severe/unstable angina pectoris or coronary artery bypassgrafting within 6 months prior to enrollment; congestive heart failure according tothe New York Heart Association (NYHA) classification ≥ 2; ventricular arrhythmiaswhich needs drug treatment; or left ventricular ejection fraction (LVEF) <50%;
• Active infection or serious infection that is not controlled by drug (≥CTCAE v5.0Grade 2）;
• History of clinically significant hepatic disease, including, but not limited to,known hepatitis B virus (HBV) infection with HBV DNA positive (copies ≥1×104/ml);known hepatitis C virus infection with HCV RNA positive (copies ≥1×103/m); or livercirrhosis;
• Mean corrected QT interval (QTc) ≥ 480 msec;
• Occurrence of central nervous system metastatic or known brain metastatic;
• Adverse events (AEs) due to previous anti-tumor therapy has not recovered to CommonTerminology Criteria for Adverse Event (CTCAE) ≤Grade 1. Alopecia, lymphocytopenia,and grade ≤2 neurotoxicity due to oxaliplatin are not included;
• Women who are pregnant or lactating;
• With blood transfusion or any blood component or cell growth factor within 14 daysprior to enrollment;
• Brachytherapy (i.e., implantation of radioactive seeds) within 60 days beforeenrollment;
• Urine routine indicates urinary protein ≥ ++, and the 24-hour urine proteinquantification is greater than 1.0 g;
• Have any other disease, metabolic disorder, physical examination anomaly, abnormallaboratory result, or any other conditions which, according to judgement of theinvestigator, renders the patient inappropriate for using the investigational productor affect interpretation of study results.