A study to evaluate the efficacy and safety of icaritin versus huachansu in the first-line treatment of unresectable hepatocellular carcinoma with poor conditions and biomarker enrichment.

This is a prospective, randomized, parallel-controlled, double-blind, double-dummy, multicenter, phase III clinical trial. Patients with poor conditions and biomarker enrichment will be randomly assigned in a 2:1 ratio to receive either icaritin or huachansu as the first-line treatment until unacceptable toxic effects and loss of clinical benefit. A total of 261 participants with 206 deaths are required. The primary endpoint is overall survival (OS) in the full analysis set (FAS) population.

Inclusion Criteria:

1. Male or female, 18 years and older;

2. HCC patients who meet the clinical diagnostic criteria of the Chinese Diagnosis and Treatment Guideline of Primary Liver Cancer (2022 edition), and/or with diagnosis confirmed histopathologically/cytologically;

3. Unresectable HCC patients;

4. Patients with a peripheral blood composite biomarker Score ≥ 2 points, 1 point each for AFP ≥ 400 ng/mL, TNF-α < 2.5 pg/mL, and IFN-γ ≥ 7.0 pg/mL ;

5. No prior first-line systemic treatment for HCC, including sorafenib, lenvatinib, donafenib, atezolizumab plus bevacizumab, sintilimab plus a bevacizumab biosimilar, camrelizumab plus apatinib, and durvalumab plus tremelimumab, oxaliplatin-based systemic chemotherapy (FOLFOX4) , icaritin, huachansu, and other anti-cancer drugs such as targeted agents, immune checkpoint inhibitors, and systemic chemotherapy;

6. Child-Pugh score ≤ 7;

7. Vital organ functions should meet the following requirements:

   ① Hematopoietic function: platelet ≥ 40×10^9/L, hemoglobin ≥ 80 g/L, white blood cell ≥ 2.0×10^9/L;

   ② Liver function: total bilirubin ≤ 1.5 times upper limit of normal (ULN) , alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) ≤ 5×ULN; albumin ≥ 28 g/L;

   ③ Renal function: Serum Creatinine ≤ 1.5×ULN, or creatinine clearance rate ≥ 50 mL/min;

8. If HBV-DNA ≥ 10^4 copies/mL (2000 IU/mL), antiviral and liver protection therapy must be used before enrollment, until HBV-DNA < 10^4 copies/mL (2000 IU/mL). In which case, the antiviral drugs should be administered continuously and liver function and hepatitis B virus load will be monitored during the study period;

9. Patients who meet one of two conditions: (A) are not or less appropriate candidates for first-line standard treatments recommended by the guidelines; (B) are not willing to receive first-line standard treatments recommended by the guidelines.

10. Surgical resection ended > 3 months, local ablation, hepatic artery intervention or radiotherapy ended > 4 weeks before randomization (implantation of radioactive particles ended > 3 months) and relevant adverse reactions having recovered. Patients without extrahepatic spread must have radiographic evidence of disease progression after local treatment;

11. Patients who had previously received adjuvant systemic therapy after surgical resection experienced the first radiographic disease progression more than 6 months after withdrawal of adjuvant therapy will be eligible for enrollment;

12. Within 2 weeks prior to randomization, no treatment with modern Chinese traditional medicine preparations with anti-tumor indications (refer to the 11th inclusion criterion when huaier granule was used as systemic adjuvant therapy), immunomodulators such as interferon-α and thymalfasin, tumor vaccines and cellular immunotherapy;

13. No blood transfusion or infusion of blood products, no use of hematopoietic growth factors (such as granulocyte colony-stimulating factor G-CSF), and no albumin infusion within 2 weeks prior to randomization;

14. ≥1 measurable lesion according to the Response Evaluation Criteria In Solid Tumors (RECIST 1.1), defined as a non-lymphoid lesion with the longest diameter ≥ 10 mm or a lymph node lesion with the short axis ≥ 15 mm; a lesion after previous radiotherapy or other loco-regional therapy which has been demonstrated progression confirmed per RECIST v1.1 with the longest diameter ≥ 10 mm scanned by dynamic-enhanced CT/ dynamic-enhanced MRI is to be deemed as a measurable lesion.

15. Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 or 1;

16. Expected survival of ≥ 12 weeks;

17. Female patients of childbearing age with a negative blood pregnancy within the first 7 days prior to randomization will be eligible; Female patients of childbearing age or male patients with female sexual partners of childbearing age should take effective contraceptive measures throughout treatment and within 3 months after the last dose;

18. Voluntary agreement to sign informed consent and the willingness and ability to comply with protocol schedules and testing;

19. No treatment with any other investigational drugs or medical devices within 4 weeks prior to randomization.

Exclusion Criteria:

1. Tumor occupancy ≥ 70% of liver, or tumor thrombus occupancy ≥ 50% of the main trunk of portal vein, or mesenteric vein or inferior vena cava tumor thrombus;
2. Moderate-to-severe ascites, i.e., the score of the indicator is > 2; Moderate-to-severe, or symptomatic pleural effusion and pericardial effusion requiring drainage;
3. Receipt of major surgery (craniotomy, thoracotomy, laparotomy, hip replacement, etc.) within 28 days prior to randomization or planned to receive major surgery during the study;
4. Other types of primary liver cancer, such as intrahepatic cholangiocarcinoma, mixed HCC and cholangiocarcinoma, fibrolamellar HCC, etc. Other malignancies within 5 years prior to signing the informed consent form or at present, excluding radically treated basal cell carcinoma of skin, squamous cell carcinoma of skin and/or radically resected carcinoma in situ;
5. Pregnant or lactating women;
6. Grade 2 or above myocardial ischemia or myocardial infarction (NCI-CTCAE v5.0), poorly-controlled arrhythmia, and/or New York Heart Association (NYHA) class III or IV cardiac insufficiency;
7. Patients who previously received allogeneic transplantation including liver transplantation, or plan to undergo liver transplantation during the study;
8. History of hepatic encephalopathy and/or hepatic nephropathy within 6 months prior to signing informed consent ;
9. HCV-RNA positive, ALT and/or AST > 2×ULN;
10. Human immunodeficiency virus (HIV) antibody positive;
11. Severe infection (≥ Grade 3 of NCI-CTCAE v5.0 criteria) at randomization;
12. Unable to swallow, chronic diarrhea or intestinal obstruction, which will significantly affect oral administration and absorption of the study drug;
13. History of gastrointestinal hemorrhage within 6 months before signing informed consent, or with clear tendency for gastrointestinal hemorrhage at present, such as: local active ulcers, stool occult blood ≥ 2+ or positive at two consecutive tests (attention should be paid to exclude the influence of food, drugs and other diseases);
14. Active autoimmune diseases requiring systemic treatment (e.g., NSAIDs, immunosuppressants, biologics, corticosteroids, etc.) except for patients receiving replacement therapy (e.g., hypothyroidism treated with thyroxine, type 1 diabetes mellitus treated with insulin, adrenal or pituitary insufficiency treated with physiologic corticosteroids, etc.);
15. Known central nervous system (CNS) metastasis; patients suspected of CNS metastasis need to undergo cerebral MRI/CT for exclusion;
16. Significant coagulation function abnormalities: international standardized ratio (INR) > 1.5 or prothrombin time (PT) > 16 s;
17. History of schizophrenia or psychiatric drug abuse;
18. Known allergy or intolerance to any ingredients of icaritin or huachansu preparations;
19. Other conditions that the investigator considers inappropriate for participation in this study.