Clinical trial NCT05161143: Donafenib Combined With TACE as Adjuvant Therapy of Patients With Hepatocellular Carcinoma
Official title: Efficacy and Safety of Donafenib Combined With TACE as Adjuvant Therapy of Patients With Hepatocellular Carcinoma at a High Risk of Recurrence After Radical Resection
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Keywords: hepatocellular carcinoma
Adjuvant therapy
Donafenib
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
Collaborators: name: Suzhou Zelgen Biopharmaceuticals Co.,Ltd
First posted: 2021-12-17
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The investigators design a phase IIB clinical study to explore the efficacy and safety of Donafenib combined with TACE as adjuvant therapy of patients with hepatocellular carcinoma at a high risk of recurrence after radical resection.

Detailed description: This trial is a single-arm, non-randomized and single-center clinical study of targeted therapy combined TACE in patients with hepatocellular carcinoma at a high risk of recurrence after radical resection.It is estimated that 30 patients who met the study criteria will be enrolled in Peking Union Medical College Hospital(PUMCH) and treated with Donafenib and TACE. The investigators will follow up and collect subjects' data monthly to evaluate the efficacy and safety of treatment, including overall survival and time to progression.

Eligibility criteria: Inclusion Criteria:

1. Age 18 \~ 75 years old (including boundary value), male and female;
2. Radical resection of liver cancer and intraoperative ablation of tumors ≤ 2cm were performed 4 \~ 8 weeks before enrollment;
3. Hepatocellular carcinoma diagnosed by pathology and meeting at least one of the following conditions:

   1. Single tumor with tumor size ≥ 5cm;
   2. Pathology showed microvascular invasion (MVI);
   3. Satellite foci were found in the specimens;
   4. Multiple lesions (≥ 3);
   5. AFP ≥ 400 ng / ml one week before operation
   6. Preoperative imaging and / or intraoperative or postoperative pathological reports found PVTT type I: tumor thrombus invaded the secondary and above branches of portal vein;
4. No anti-tumor treatment was received before operation;
5. Liver function grade child Pugh a;
6. Physical condition (PS) score of Eastern cancer cooperation group (ECoG) was 0-1;
7. Imaging examination ≥ 4 weeks after operation confirmed that there was no recurrence and metastasis;
8. The estimated survival time shall not be less than 3 months;
9. With sufficient organ function reserve, the laboratory test values within 14 days before treatment must meet the following standards:

   1. Blood routine examination: Hb≥100 g/L; ANC≥1.5 × 109 /L; PLT≥75 × 109 /L
   2. Biochemical examination: ALB ≥28g/L; ALT and AST \< 5 × ULN; TBIL ≤2 × ULN; creatinine ≤ 1.5 × ULN or creatinine clearance (CCR) ≥ 50 ml / min
   3. The electrolyte is basically normal or normal after treatment;
   4. Urinary protein \< 2 + or 24-hour urinary protein quantitative test ≤ 1.0 g / L (for patients with urinary protein ≥ 2 +, 24-hour urinary protein quantitative test should be carried out, and they can be selected only when it is ≤ 1.0 g / L);
   5. Coagulation function:

   international standard ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN activated partial coagulation time (APTT) ≤ 1.5 × ULN
10. Patients with HBsAg positive should continue antiviral treatment after operation and take first-line antiviral drugs such as entecavir or tenofovir or propofol tenofovir fumarate;
11. The patients were enrolled voluntarily, could provide written informed consent, and could understand and comply with the trial protocol to follow-up.

Exclusion Criteria:

1. The pathological diagnosis was fiberboard HCC, sarcomatoid HCC, hepatocellular carcinoma intrahepatic cholangiocarcinoma (HCC-ICC);
2. Positive margin or tumor rupture;
3. Reoperation of recurrent liver cancer;
4. Previous liver transplantation;
5. AFP did not return to normal at 4 weeks and did not return to normal at 6 weeks after operation;
6. Previously received systemic therapy for HCC, including targeted drug therapy such as Sorafenib, Lenvatinib and Regorafenib, or immunotherapy such as anti-PD-1, anti-PD-L1 and anti-CTLA-4, except antiviral therapy; If the patient has previously used traditional Chinese medicine with anti-tumor indications, it must be more than 4 weeks after the completion of treatment and before the medication in this study, and the adverse events caused by treatment have not recovered to ≤ CTCAE level 1;
7. Received other adjuvant therapy (except antiviral therapy), including adjuvant local therapy;
8. There were tumor thrombi in the main portal vein and primary branches, inferior vena cava, hepatic vein or bile duct, lymph node invasion or extrahepatic metastasis before operation;
9. 5 years of suffering from other malignancies, unless the patient has received the possibility of curative treatment and there is no evidence of the disease within 5 years, the time requirement (i.e. 5 years) does not apply to successful basal cell carcinoma, cutaneous squamous cell carcinoma, superficial bladder cancer, cervical carcinoma in situ or other orthotopic cancer.
10. Previous history of severe mental illness;
11. Suffering from diseases affecting the absorption, distribution, metabolism or clearance of the study drug (such as severe vomiting, chronic diarrhea, intestinal obstruction, absorption disorder, etc.);
12. Taking drugs that may prolong QTc and / or induce tip twist transition ventricular tachycardia (TDP) or drugs that affect drug metabolism at the same time;
13. The patient has known or suspected allergy to tyrosine kinase inhibitor (TKI) drugs, or is allergic to the excipients of the study drugs;
14. There are uncontrollable hepatic encephalopathy, hepatorenal syndrome, ascites, pleural effusion or pericardial effusion;
15. Have active bleeding or abnormal coagulation function, have bleeding tendency or are receiving thrombolytic, anticoagulant or antiplatelet therapy;
16. Have a history of gastrointestinal hemorrhage or have a clear tendency of gastrointestinal bleeding in the past 4 weeks (e.g. local active ulcer lesions, fecal occult blood + + or more, gastroscopy should be performed if continuous fecal occult blood +, or other conditions that may cause gastrointestinal bleeding determined by the researcher (e.g. severe gastric fundus / esophageal varices);
17. Gastrointestinal perforation, abdominal fistula or abdominal abscess occurred in the past 6 months;
18. Thrombosis or thromboembolism events occurred in the past 6 months, such as stroke and / or transient ischemic attack, deep vein thrombosis, pulmonary embolism, etc;
19. Uncontrolled cardiovascular disease judged by the researcher. Including but not limited to the following situations:

    1. acute myocardial infarction in the past 6 months;
    2. Severe / unstable angina pectoris or coronary artery bypass grafting;
    3. Congestive heart failure (NYHA \> 2);
    4. Arrhythmias with poor control or requiring pacemaker treatment;
    5. Hypertension (systolic blood pressure ≥ 140 mmHg and / or diastolic blood pressure ≥ 90 mmHg) ";
20. Active infection requiring treatment

    1. Active hepatitis B (HBsAg positive and abnormal liver function): if the HBV-DNA is ≥ 104 copies / ml within 14 days before treatment, the patient shall first undergo antiviral treatment, reduce it to \< 104 copies / ml, and then enter the study, continue antiviral treatment and monitor liver function and serum HBV-DNA level;
    2. Active hepatitis C (HCV-RNA ≥ 103 copies / ml) with abnormal liver function \[ALT or ast \> 3 × ULN with TBIL \> 2 × ULN or clinical jaundice\]);
21. pregnant or lactating women, and female or male patients with fertility are unwilling or unable to take effective contraceptive measures;

Primary outcomes:
measure: 1 year RFS rate
timeFrame: 1 year
Secondary outcomes:
measure: RFS
timeFrame: 3 years
measure: OS
timeFrame: 3 years
measure: TTR
timeFrame: 3 years
measure: 2/3 year RFS rate
timeFrame: 2/3 years
measure: AE
timeFrame: 3 years
measure: AFP
timeFrame: 3 years
Other outcomes:
Locations:
city: Beijing
country: China
facility: Chinese Academy of Medical Sciences & Peking Union Medical College Hospital
Study officials:
affiliation: Peking Union Medical College Hospital
name: Yilei Mao, MD
role: PRINCIPAL_INVESTIGATOR
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