Hepatocellular Carcinoma
Conditions
Keywords
Hepatocellular carcinoma, Targeted therapy plus immunotherapy, Zinc supplementation, Objective response rate
Brief summary
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 16. 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.
Interventions
DRUGOral elemental zinc supplementation, 20 mg/day
Participants will receive oral elemental zinc supplementation at a dose of 20 mg/day. Zinc gluconate tablets will be administered orally, 1 tablet twice daily after meals.
DRUGOral elemental zinc supplementation, 30 mg/day
Participants will receive oral elemental zinc supplementation at a dose of 30 mg/day. Zinc gluconate tablets will be administered orally, 1 tablet three times daily after meals.
DRUGStandard-of-care targeted therapy plus immunotherapy
The background targeted therapy plus immunotherapy regimen will be determined by the investigator based on the participant's clinical condition, applicable treatment guidelines, prescribing information, and routine clinical practice at the study center. Permitted regimens include sintilimab plus bevacizumab or a bevacizumab biosimilar, tislelizumab plus lenvatinib, and atezolizumab plus bevacizumab. The background treatment regimen should remain unchanged during the study whenever clinically feasible. If treatment modification is required because of toxicity, intolerance, disease progression, drug availability, or other clinical considerations, the reason for and details of the modification will be documented in the case report form (CRF).
Sponsors
Anhui Provincial Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female participants aged 18-75 years who are able to understand the study and voluntarily provide written informed consent. 2. Histologically or cytologically confirmed hepatocellular carcinoma (HCC) that is unresectable, recurrent, or metastatic. 3. Estimated life expectancy of more than 3 months. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 5. At least one measurable lesion according to RECIST v1.1. The lesion must not have received prior local therapy; if previously treated locally, there must be documented disease progression, defined as an increase of ≥20% in the sum of diameters from the post-treatment nadir with an absolute increase of ≥5 mm, or the appearance of a new lesion meeting RECIST v1.1 measurability criteria. 6. Child-Pugh class A, score 5-6, with no clinically significant ascites, hepatic encephalopathy, or recent hepatic decompensation. 7. Barcelona Clinic Liver Cancer (BCLC) stage B that is unsuitable for or no longer suitable for local treatment, or BCLC stage C. 8. 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. Prior local treatments, including surgery, ablation, transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), or radiotherapy, are permitted provided that treatment was completed ≥4 weeks before enrollment and related toxicities have recovered to Grade ≤1 or are considered by the investigator not to interfere with study participation. 9. 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. 10. 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. 11. Baseline testing for serum zinc, serum copper, and ceruloplasmin must be completed. 12. 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. 13. Able to take the study medication orally and willing to comply with study treatment, follow-up visits, imaging assessments, and blood sample collection requirements. 14. 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.
Exclusion criteria
1. 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. 2. 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. 3. Active autoimmune disease, a history of severe immune-related adverse events, or requirement for systemic immunosuppressive therapy within 14 days before screening. 4. 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. 5. 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. 6. 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. 7. 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. 8. Known severe hypersensitivity to zinc preparations or any drug used in the background targeted therapy plus immunotherapy regimen. 9. 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. 10. 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. 11. 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. 12. 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. 13. Uncontrolled central nervous system metastases or leptomeningeal metastases, or symptomatic CNS disease. 14. Pregnancy, breastfeeding, or a positive pregnancy test during screening. 15. 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. 16. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate at Week 16 | At Week 16 after initiation of study treatment | Proportion of participants achieving complete response (CR) or partial response (PR) at Week 16 according to RECIST v1.1. ORR = (CR + PR) / total number of participants in the analysis set × 100%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) at Week 8 | At Week 8 after initiation of study treatment. | Proportion of participants achieving complete response (CR) or partial response (PR) at Week 8 according to RECIST v1.1. |
| Objective Response Rate (ORR) by mRECIST | At Weeks 8 and 16 after initiation of study treatment. | Proportion of participants achieving complete response (CR) or partial response (PR) according to mRECIST for hepatocellular carcinoma. |
| Disease Control Rate | At Weeks 8 and 16 after initiation of study treatment. | Proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD), assessed according to RECIST v1.1 and mRECIST. |
| Progression-Free Survival | From enrollment until disease progression or death, whichever occurs first. | Time from enrollment to the first documented disease progression according to RECIST v1.1 or death from any cause, whichever occurs first. |
| Overall Survival | From enrollment until death from any cause. | Time from enrollment to death from any cause. Participants who are alive will be censored at the date of last known survival. |
| Change in Serum Zinc Level | At Weeks 4, 8, 12, and 16 after initiation of study treatment. | Absolute and relative changes in serum zinc levels from baseline. Time Frame: |
| Incidence of Copper Deficiency | At Weeks 4, 8, 12, and 16 after initiation of study treatment. | Proportion of participants with serum copper or ceruloplasmin levels below the lower limit of normal during treatment. |
| Zinc Correction Rate | At Weeks 4, 8, 12, and 16 after initiation of study treatment. | Proportion of participants with baseline serum zinc \<80 μg/dL who achieve a serum zinc level ≥80 μg/dL at the specified visit. |
| Change in Peripheral Blood CD3+, CD4+, and CD8+ T-cell Counts | At Weeks 1, 4, 8, 12, and 16 after initiation of study treatment. | Change from baseline in the absolute counts of peripheral blood CD3+, CD4+, and CD8+ T cells, measured by flow cytometry. |
| Change in Ki-67+ Cells Among Peripheral Blood PD-1+CD8+ T Cells | At Weeks 1, 4, 8, 12, and 16 after initiation of study treatment. | Change from baseline in the proportion of Ki-67+ cells among peripheral blood PD-1+CD8+ T cells, measured by flow cytometry. |
| Fold Change in Ki-67+ Cells Among Peripheral Blood PD-1+CD8+ T Cells | At Week 1 after initiation of study treatment. | — |
Countries
China
Contacts
CONTACTYao Liu, Dr
CONTACTHua Lu, MD
PRINCIPAL_INVESTIGATORLianxin Liu
The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital)
Outcome results
None listed