Continuation of First-line Therapy With Radiotherapy Versus Early Switch to Second-line Therapy in Oligoprogressive HCC

Last updated: July 31, 2025
Sponsor: Shandong Cancer Hospital and Institute
Overall Status: Active - Recruiting

Phase

3

Condition

Neoplasm Metastasis

Carcinoma

Cancer Treatment

Treatment

Systemic therapy (early switch to regorafenib)

Systemic therapy (Continuation of current first-line systemic therapy)

Systemic therapy (Early switch to second-line systemic therapy)

Clinical Study ID

NCT06841172
SDZLEC2025-025-02
  • Ages 18-75
  • All Genders

Study Summary

This multicenter, prospective, randomized, controlled, open-label, two-arm Phase III clinical trial is designed to evaluate whether adding radiotherapy to oligoprogressive lesions while continuing first-line systemic therapy at the time of oligoprogression can effectively prolong progression-free survival compared to early switching to second-line systemic therapy in oligoprogressive hepatocellular carcinoma.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Histological or cytological confirmation of primary hepatocellular carcinoma (HCC), or diagnosis based on the Clinical Diagnosis and Treatment Guidelinesfor Primary Liver Cancer (2024 edition) issued by the National HealthCommission of the People's Republic of China.
  1. BCLC stage C at the time of first-line systemic treatment.
  1. Oligoprogression must be confirmed by imaging or histopathology duringfirst-line systemic therapy (FLST). The number of oligoprogressive lesions islimited to 1-5, involving no more than 1-3 organs or systems. These lesions mayrepresent either new metastatic sites or progression of pre-existing lesions.In addition, they must fit one of the two classifications defined in theESTRO-EORTC consensus on oligometastases: repeat oligoprogression or inducedoligoprogression. Oligoprogression may occur within intrahepatic lesions. Inthe case of lymph node progression, each lymphatic drainage region isconsidered a separate lesion. For example, the para-aortic lymph nodes (number 16a and number 16b) are each counted as separate lymph node regions.
  1. Patients must have experienced oligoprogression while receiving their currentFLST and must not have previously received any other FLST that resulted indisease progression. Additionally, the current FLST must have maintaineddisease stability (SD) for at least three months prior to the occurrence ofoligoprogression. Furthermore, the expected survival time must be ≥6 months.
  1. Oligoprogressive lesions must be eligible for radiotherapy and should have atleast one measurable lesion that meets RECIST v1.1 criteria; Bone metastaseswithout soft tissue formation are eligible but are considered non-measurablelesions; Bone metastases with soft tissue formation that meet RECIST v1.1measurable criteria are considered measurable lesions.
  1. Liver function must be assessed as Child-Pugh score ≤7 points.
  1. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0-1.
  1. Participants must be able to understand and voluntarily sign a written informedconsent prior to the initiation of any study-specific procedures and must agreeto comply with the treatment and follow-up requirements of the study.
  1. Male or female patients between 18 and 75 years of age.
  1. Availability of tumor and blood samples for biomarker assessment.

Exclusion

Exclusion Criteria:

  1. Patients who received FLST as adjuvant treatment after curative surgery forHCC.
  1. Tumor progression occurring within 3 months after initiation of FLST.
  1. Patients with combined hepatocellular-cholangiocarcinoma (cHCC-CC)
  1. History of grade ≥3 serious adverse events due to FLST.
  1. Presence of brain, peritoneal or omental metastases with bleeding after FLST.
  1. Previous radiation therapy to the site of the oligoprogressive lesion.
  1. Active untreated hepatitis B, defined as HBsAg positive with HBV DNA levelsabove the upper limit of normal in the participating center's laboratory.
  1. Oligoprogressive lesions not amenable to radiotherapy.
  1. Alpha-fetoprotein (AFP) level ≥10,000 ng/mL at the time of oligoprogression.
  1. Diagnosis of malignancy other than liver cancer within 3 years prior toenrollment (excluding curatively treated basal cell carcinoma, squamous cellcarcinoma of the skin, and/or carcinoma in situ).
  1. Currently participating in any interventional clinical research treatment orhaving received any other investigational drug or investigational devicetherapy within the last 4 weeks prior to enrollment.
  1. Presence of autoimmune disease or other conditions requiring long-term steroiduse.
  1. Severe impairment of the heart, lungs, kidneys, or other vital organs, activeinfections (other than viral hepatitis), or other serious comorbidities thatrender the patient unable to tolerate treatment.
  1. known or suspected allergy to any study drug or to any drug related to thisstudy.
  1. History of organ transplantation
  1. Pregnant or breastfeeding women
  1. Any other factor that the investigator believes may affect the enrollment ofpatients or the evaluation of study results.

Study Design

Total Participants: 132
Treatment Group(s): 4
Primary Treatment: Systemic therapy (early switch to regorafenib)
Phase: 3
Study Start date:
July 21, 2025
Estimated Completion Date:
July 01, 2028

Study Description

Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage due to its aggressive nature and lack of early symptoms, making most patients ineligible for curative treatment. In recent years, novel therapeutic approaches, including targeted therapy, immunotherapy and combination regimens, have improved systemic treatment outcomes for advanced HCC, thereby increasing patient survival. However, the objective response rate of first-line systemic treatments remains limited at approximately 20-35%, and most patients inevitably develop resistance and disease progression during treatment.

For patients undergoing first-line systemic therapy (FLST) who develop oligoprogression - defined as the progression of a limited number of lesions during systemic treatment - the standard approach is typically to move to second-line systemic therapy (SLST). However, available SLST options remain limited, with median progression-free survival (PFS) of only 2.6-3.1 months, underscoring the urgent need for optimized treatment strategies.

The investigators hypothesize that administering local radiotherapy to oligoprogressive lesions while continuing current FLST - provided it remains effective for non-progressing disease - could delay the need for SLST and potentially improve both PFS and OS. This treatment approach has been validated in prospective studies in other malignancies. In addition, our recent multicenter retrospective study published in the Red Journal demonstrated that maintaining FLST in combination with radiotherapy for oligoprogressive lesions significantly prolonged PFS in patients with HCC.

Based on these findings, this study aims to conduct a prospective, randomized, controlled Phase III clinical trial in patients with oligoprogressive HCC following FLST. The trial will evaluate whether adding radiotherapy to oligoprogressive lesions while continuing current FLST provides clinical benefit compared to early transition to SLST.

The primary endpoint of this trial is PFS. The secondary endpoints include OS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety (assessed according to CTCAE 5.0).

This trial will enroll patients with HCC who experience oligoprogression while receiving FLST, provided they have received at least three months of FLST prior to oligoprogression. Patients will be randomized 1:1 to one of two cohorts:

Cohort 1: Radiotherapy targeting oligoprogressive lesions while continuing current FLST.

Cohort 2: Early transition to SLST. In addition, exploratory objectives include the collection and analysis of circulating tumor DNA (ctDNA) to assess dynamic changes at baseline (time of oligoprogression), at first follow-up after radiotherapy, and at subsequent disease progression. A subset of participants will also undergo biopsies of both primary tumors and progressive lesions at baseline (oligoprogression) and at subsequent progression to further investigate molecular and genomic changes.

Connect with a study center

  • Jinan, Shandong 0531

    Jinan, Shandong
    China

    Active - Recruiting

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