Nanocrystalline Megestrol Acetate Versus Placebo for Anorexia in Patients With Unresectable Hepatocellular Carcinoma Receiving TACE Combined With Targeted and Immunotherapy

Inclusion criteria

• Patients with unresectable primary hepatocellular carcinoma (HCC) confirmed by imaging or histopathology
• No previous receipt of immunotherapy and/or targeted drug therapy
• Child-Pugh score ≤ 7
• At least one measurable lesion per RECIST 1.1 criteria; lesions without prior radiotherapy, cryotherapy or other local treatment
• Single intrahepatic lesion < 10 cm, or fewer than 10 intrahepatic lesions with tumor burden < 50%
• Meet precachexia criteria: non-volitional weight loss ≤ 5% in 6 months, plus systemic inflammation (CRP > 5 mg/L) or decreased appetite (FAACT-A/CS-12 score ≤ 37 points)
• Meet cachexia criteria: accompanied by decreased appetite or systemic inflammation, with either non-volitional weight loss > 5% in 6 months or BMI < 18.5 kg/m² plus weight loss > 2%
• Voluntarily participate and sign informed consent
• Age ≥ 18 years, male or female
• Able to swallow tablets normally
• ECOG performance status 0 or 1
• Life expectancy ≥ 12 weeks
• Adequate major organ function without blood products or colony-stimulating factors within 14 days
• Hematology: ANC ≥ 1.5×10⁹/L, Hb ≥ 80 g/L, PLT ≥ 50×10⁹/L
• Liver function: TBIL ≤ 1.5×ULN, AST/ALT ≤ 5.0×ULN, ALB ≥ 28 g/L
• Coagulation function: INR, PT or aPTT ≤ 1.5×ULN
• Renal function: SCr ≤ 1.5×ULN or creatinine clearance ≥ 60 mL/min
• Urine protein ≤ 1+ or 24-hour urine protein < 1.0 g
• Cardiac function: LVEF ≥ 50%
• Females of childbearing potential with negative pregnancy test within 3 days before first dosing
• Fertile male and female patients agree to effective contraception from screening to 120 days after last study drug
• HBV/HCV infected patients receive stable antiviral therapy without drug interaction

Exclusion criteria

• Active or untreated CNS metastases; inadequately controlled metastatic brain or leptomeningeal disease
• Uncontrolled tumor-related pain
• Thromboembolic disease, ascites or lower limb edema within 6 months
• History of other malignancies within 5 years before randomization, except curable low-risk tumors
• Unresolved adverse toxicities from prior antitumor therapy not recovered to ≤ Grade 1 (CTCAE v5.0), excluding alopecia
• Pregnant, breastfeeding females or those planning pregnancy during the study
• Any unstable medical, psychiatric or social condition that may interfere with study participation
• Positive HIV infection
• Major surgery within 28 days prior to randomization
• Severe cardiovascular disease, myocardial infarction, unstable arrhythmia, angina or cerebrovascular events
• Severe systemic infection within 4 weeks before dosing or active infection requiring systemic anti-infective treatment
• Impaired gastrointestinal absorption, long-term tube feeding, parenteral nutrition or eating disorders
• Concomitant use of other appetite-enhancing or weight-stimulating agents
• Cushing's syndrome, adrenal or pituitary insufficiency, poorly controlled diabetes
• Uncontrolled hypertension despite oral antihypertensive treatment
• Esophagogastric varices, severe ulcers, gastrointestinal bleeding, obstruction, perforation or fistula within 6 months
• Known hypersensitivity to any component of the investigational product
• Any other condition considered inappropriate for enrollment by the investigator.