icaritin soft capsule versus huachansu tablet in the first-line treatment of unresectable hepatocellular carcinoma with poor conditions and biomarker enrichment (biomarker enrichment study of poor prognosis hcc patients, bestpop)

Conditions: Hepatocellular Carcinoma

Summary: 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.

Eligibility criteria:
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.

Keywords: icaritin, poor conditions, composite biomarker first-line treatment