A Randomized Controlled Trial Evaluating Different Doses of Oral Zinc Supplementation in Combination With Targeted Immunotherapy for Unresectable or Advanced Hepatocellular Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Objective Response Rate (ORR) at Week 18
研究概览
简要总结
This study will look at whether adding daily oral zinc supplements to targeted therapy plus immunotherapy may help people with unresectable or advanced hepatocellular carcinoma, a common type of liver cancer.
About 60 participants will take part in this study. Participants will be randomly assigned to one of three groups. One group will receive targeted therapy plus immunotherapy without extra zinc. The other two groups will receive the same type of cancer treatment together with either 20 mg or 30 mg of elemental zinc each day.
The main goal is to compare how many participants have their tumors shrink or disappear by Week 18. Researchers will also look at tumor response at earlier time points, how long the cancer remains under control, overall survival, and treatment safety.
Blood tests will be used to measure zinc and copper levels during the study. Researchers will also study changes in immune cells, including T cells, to better understand whether zinc supplementation may affect the body's immune response to cancer treatment.
This study is designed to explore whether oral zinc supplementation is safe and may improve the effects of targeted therapy plus immunotherapy. The results may help determine which zinc dose should be studied in larger clinical trials.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female participants aged 18-75 years who are able to understand the study and voluntarily provide written informed consent.
- •Histologically or cytologically confirmed hepatocellular carcinoma (HCC) that is unresectable, recurrent, or metastatic.
- •Estimated life expectancy of more than 3 months.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •At least one measurable lesion as defined by RECIST v1.1, with no prior local treatment to the measurable lesion.
- •Child-Pugh class A, score 5-6, with no clinically significant ascites, hepatic encephalopathy, or recent hepatic decompensation.
- •Barcelona Clinic Liver Cancer (BCLC) stage B that is unsuitable for or no longer suitable for local treatment, or BCLC stage C.
- •No prior systemic antitumor therapy for unresectable, recurrent, or metastatic HCC, including immune checkpoint inhibitors, anti-VEGF/VEGFR-targeted therapy, tyrosine kinase inhibitors (TKIs), systemic chemotherapy, or other systemic anticancer agents.
- •Participants must not have received any prior local antitumor treatment, including surgery, ablation, transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), or radiotherapy.
- •Planned treatment with targeted therapy plus immunotherapy in accordance with applicable treatment guidelines and clinical practice, with the specific background antitumor regimen determined by the investigator before enrollment. The background regimen should not be changed arbitrarily during the study.
- •If the background treatment regimen includes bevacizumab or another anti-VEGF monoclonal antibody, the participant must undergo upper gastrointestinal endoscopy during screening or have an evaluable endoscopic examination performed within 6 months before screening. Participants with esophagogastric varices requiring treatment may be enrolled only after appropriate management and when the investigator considers the bleeding risk to be adequately controlled.
- •Baseline testing for serum zinc, serum copper, and ceruloplasmin must be completed.
- •Adequate major organ function to receive targeted therapy plus immunotherapy, including:
- •Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L
- •Platelet count ≥75 × 10⁹/L
- •Hemoglobin ≥90 g/L
- •AST and ALT ≤5 × upper limit of normal (ULN)
- •Total bilirubin ≤1.5 × ULN, or considered by the investigator to be consistent with Child-Pugh class A and safe for enrollment
- •Serum creatinine ≤1.5 × ULN, or creatinine clearance ≥50 mL/min
- •INR ≤1.5, unless the participant is receiving stable anticoagulation therapy and the investigator considers the associated risk to be acceptable.
- •Able to take the study medication orally and willing to comply with study treatment, follow-up visits, imaging assessments, and blood sample collection requirements.
- •Participants of childbearing potential must agree to use effective contraception during the study and for the protocol-specified period after the last dose of study treatment.
排除标准
- •Primary liver cancer histology other than predominant HCC, such as intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma, or the presence of another active malignancy requiring systemic treatment.
- •Prior systemic antitumor therapy for unresectable, recurrent, or metastatic HCC. Participants who have previously received PD-1, PD-L1, or CTLA-4 inhibitors, or systemic anti-VEGF/VEGFR therapy, will be excluded.
- •Active autoimmune disease, a history of severe immune-related adverse events, or requirement for systemic immunosuppressive therapy within 14 days before screening.
- •Clinically significant ascites, such as ascites requiring repeated paracentesis, albumin infusion, or showing recent rapid worsening; current or previous hepatic encephalopathy, hepatorenal syndrome, or other clear evidence of hepatic decompensation.
- •Confirmed copper deficiency, Wilson disease, Menkes disease, or other clinically significant disorders of copper metabolism; participants currently receiving zinc salts for the treatment of Wilson disease will be excluded.
- •Use of zinc-containing supplements, multivitamin/mineral preparations, zinc-containing denture adhesives, or other supplements that may significantly affect zinc or copper levels within 14-28 days before screening, if such products cannot be discontinued.
- •Conditions that may significantly affect oral drug absorption or adherence, including persistent vomiting, severe diarrhea, short bowel syndrome, active inflammatory bowel disease, gastrointestinal obstruction, severe dysphagia, or any condition that, in the investigator's judgment, would prevent regular oral administration of the study medication.
- •Known severe hypersensitivity to zinc preparations or any drug used in the background targeted therapy plus immunotherapy regimen.
- •Active severe infection. Participants with HBV DNA positivity accompanied by elevated viral load and ALT and/or AST above the upper limit of normal, with evidence of active hepatic inflammation, will be excluded. Participants who are HBsAg-positive but HBV DNA-negative with normal liver biochemistry will not be excluded solely on the basis of HBV carrier status.
- •Untreated or inadequately treated esophagogastric varices, or other portal hypertension-related lesions considered by the investigator to confer a high bleeding risk; gastrointestinal bleeding, hemoptysis, intracranial hemorrhage, or any other Grade ≥3 bleeding event within 6 months before screening.
- •Uncontrolled hypertension, severe cardiovascular or cerebrovascular disease, recent myocardial infarction, stroke, or pulmonary embolism, severe arrhythmia, NYHA class III-IV heart failure, or any condition that, in the investigator's judgment, would preclude safe treatment with anti-VEGF therapy or a TKI.
- •Major surgery within 28 days before screening, unhealed open wounds, active peptic ulcer disease, high risk of gastrointestinal perforation or fistula, or any condition that may adversely affect the safety of bevacizumab or other anti-VEGF therapy.
- •Uncontrolled central nervous system metastases or leptomeningeal metastases, or symptomatic CNS disease.
- •Pregnancy, breastfeeding, or a positive pregnancy test during screening.
- •Planned use during the study of any antitumor treatment, investigational drug, or nutritional intervention outside the protocol that could interfere with assessment of antitumor efficacy.
- •Any other condition that, in the investigator's judgment, makes the participant unsuitable for study enrollment, including severe psychiatric illness, poor adherence, inability to complete follow-up, drug or alcohol abuse, or a clearly increased safety risk.
研究组 & 干预措施
Zinc 30 mg/day Group
Participants will receive standard-of-care targeted therapy plus immunotherapy together with oral elemental zinc supplementation at a dose of 30 mg/day.
干预措施: Standard-of-care targeted therapy plus immunotherapy (Drug)
Control Group
Participants will receive standard-of-care targeted therapy plus immunotherapy without additional zinc supplementation.
干预措施: Standard-of-care targeted therapy plus immunotherapy (Drug)
Zinc 20 mg/day Group
Participants will receive standard-of-care targeted therapy plus immunotherapy together with oral elemental zinc supplementation at a dose of 20 mg/day.
干预措施: Oral elemental zinc supplementation, 20 mg/day (Drug)
Zinc 20 mg/day Group
Participants will receive standard-of-care targeted therapy plus immunotherapy together with oral elemental zinc supplementation at a dose of 20 mg/day.
干预措施: Standard-of-care targeted therapy plus immunotherapy (Drug)
Zinc 30 mg/day Group
Participants will receive standard-of-care targeted therapy plus immunotherapy together with oral elemental zinc supplementation at a dose of 30 mg/day.
干预措施: Oral elemental zinc supplementation, 30 mg/day (Drug)
结局指标
主要结局
Objective Response Rate (ORR) at Week 18
时间窗: At Week 18 after initiation of study treatment
Proportion of participants achieving complete response (CR) or partial response (PR) at Week 18 according to RECIST v1.1. ORR = (CR + PR) / total number of participants in the analysis set × 100%.
次要结局
- Progression-Free Survival(From enrollment until disease progression or death, whichever occurs first.)
- Overall Survival(From enrollment until death from any cause.)
- Objective Response Rate (ORR) at Week 9(At Week 9 after initiation of study treatment.)
- Objective Response Rate (ORR) by mRECIST(At Weeks 9 and 18 after initiation of study treatment.)
- Disease Control Rate(At Weeks 9 and 18 after initiation of study treatment.)
- Change in Serum Zinc Level(At Weeks 3, 6, 9,12,15 and 18 after initiation of study treatment.)
- Incidence of Copper Deficiency(At Weeks 3, 6, 9,12,15 and 18 after initiation of study treatment.)
- Zinc Correction Rate(At Weeks 3, 6, 9,12,15 and 18 after initiation of study treatment.)
- Change in Peripheral Blood CD3+, CD4+, and CD8+ T-cell Counts(At Weeks 3, 6, 9,12,15 and 18 after initiation of study treatment.)
- Change in Ki-67+ Cells Among Peripheral Blood PD-1+CD8+ T Cells(At Weeks 3, 6, 9,12,15 and 18 after initiation of study treatment.)
- Fold Change in Ki-67+ Cells Among Peripheral Blood PD-1+CD8+ T Cells(At Week 3 after initiation of study treatment.)