Personalized adaptive second-line treatments for advanced liver cancer

The HCC-SIGHT: A Therapy Platform Trial for Hepatocellular Carcinoma Guided by Stratification Imaging and Genetic Horizon Testing

This trial tries different personalized second-line treatments to find which work best for people with advanced hepatocellular carcinoma after first-line immunotherapy-based regimens stop working.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 350 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fudan University (other)
• Drugs / interventions: immunotherapy
• Locations: 1 site (Shanghai, Shanghai Municipality)
• Trial ID: NCT07328009 on ClinicalTrials.gov

What this trial studies

This is an open-label, multi-arm phase II Bayesian adaptive platform that compares several experimental regimens against a common control for patients with advanced HCC who progressed after first-line therapy. Randomization weights shift over time to favor regimens showing better interim objective response rates, underperforming arms are dropped, and new arms may be added. The protocol collects tumor tissue, circulating tumor DNA, and quantitative imaging features at baseline and on treatment to discover biomarker signatures that predict response. Regimens with high predictive probability of success may graduate for further development, enabling faster, biomarker-informed matching of second-line therapies.

Who should consider this trial

Good fit: Adults (≥18) with unresectable or metastatic HCC who progressed after first-line anti-PD-1/PD-L1 combinations (with anti-VEGF, TKI, or anti-CTLA-4), with at least one measurable RECIST v1.1 lesion, Child-Pugh score 5–7, and ECOG performance status 0–2 are the ideal candidates.

Not a fit: Patients with decompensated liver disease (Child-Pugh >7), poor performance status (ECOG >2), no measurable target lesion, or who cannot tolerate TKIs or immunotherapy are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, the platform could identify personalized second-line options that increase response rates and speed the development of more effective therapies for advanced HCC.

How similar studies have performed: Individual agents like regorafenib and lenvatinib and some immune-plus-TKI combinations have shown activity in HCC, but using an adaptive, biomarker-driven platform to match therapies is relatively novel in this disease.

Eligibility criteria

Inclusion Criteria:

* Written informed consent obtained.
* Age ≥ 18 years at time of study entry.
* Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/ cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic patients.
* Patients who have previously received first-line therapy with anti-PD-1/PD-L1 combined with anti-VEGF antibodies, or anti-PD-1/PD-L1 combined with TKI, or anti-PD-1/PD-L1 combined with anti-CTLA-4 antibodies and experienced disease progression; or disease recurrence within 6 months after completion of neoadjuvant/adjuvant immunotherapy.
* At least one measurable (per RECIST v1.1) target lesion that has not been previously treated with local therapy or, if the target lesion is within the field of previous local therapy, has subsequently progressed in accordance with RECIST v1.1.
* Child-Pugh scores 5-7, performance status (PS) ≤ 2 (ECOG scale).
* Subjects with chronic HBV infection must have HBV DNA viral load \< 100 IU/mL at screening. In addition, they must be on antiviral therapy per regional standard of care guidelines prior to initiation of study therapy.
* Life expectancy of at least 12 weeks.
* Adequate blood count, liver-enzymes, and renal function: absolute neutrophil count ≥ 1,500/L, platelets ≥60 x103/L; Total bilirubin ≤ 3x upper normal limit; Aspartate Aminotransferase (SGOT), Alanine aminotransferase (SGPT) ≤ 5 x upper normal limit (ULN); International normalized ratio (INR) ≤1.25; Albumin ≥ 31 g/dL; Serum Creatinine ≤ 1.5 x institutional ULN or creatinine clearance (CrCl) ≥ 30 mL/min (if using the Cockcroft-Gault formula)
* Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
* Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment, adherence to contraceptive measures, scheduled visits and examinations including follow up.

Exclusion Criteria:

* Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
* Patients on a liver transplantation list or with advanced liver disease.
* History of cardiac disease, including clinically significant gastrointestinal bleeding within 4 weeks prior to start of study treatment
* Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months Prior to the first dose of study drug with the exception of thrombosis of a segmental portal vein.
* Patients with second primary cancer, except adequately treated basal skin cancer or carcinoma in-situ of the cervix.
* Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV).
* Participation in another clinical study with an investigational product during the last 30 days before inclusion or 7 half-lifes of previously used trial medication, whichever is longer.
* Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study Treatment or interpretation of patient safety or study results, including but not limited to: a) history of interstitial lung disease b) Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) coinfection (i.e double infection) c) known acute or chronic pancreatitis d) active tuberculosis e) any other active infection (viral, fungal or bacterial) requiring systemic therapy f) history of allogeneic tissue/solid organ transplant g) diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment. h) Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Exceptions: Subjects with vitiligo, hypothyroidism, diabetes mellitus type I or resolved childhood asthma/atopy are an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with Hashimoto thyroiditis, hypothyroidism stable on hormone replacement or psoriasis not requiring treatment are not excluded from the study. i) Live vaccine within 30 days prior to the first dose of treatment or during study treatment. j) History or clinical evidence of Central Nervous System (CNS) metastases Exceptions are: Subjects who have completed local therapy and who meet both of the following criteria: I. are asymptomatic and II. have no requirement for steroids 6 weeks prior to start of treatment. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS.
* Medication that is known to interfere with any of the agents applied in the trial.
* Any other efficacious cancer treatment except protocol specified treatment at study start.
* Patient has received any other investigational product within 28 days of study entry.
* Female subjects who are pregnant, breast-feeding or male/female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). \[Acceptable methods of contraception are: implants, injectable contraceptives, combined oral contraceptives, intrauterine pessars (only hormonal devices), sexual abstinence or vasectomy of the partner\]. Women of childbearing potential must have a negative pregnancy test (serum β-HCG) at screening.
* Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

Where this trial is running

Shanghai, Shanghai Municipality

• Zhongshan Hospital, Fudan University — Shanghai, Shanghai Municipality, China (RECRUITING)

Study contacts

• Study coordinator: Peng Wang, MD

Conditions: Hepato Cellular Carcinoma