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

NCT06841172 | Recruiting Phase 3

• 1 other identifier: SDZLEC2025-025-02
• Study Type: interventional
• Target: 132
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

OligoProgressive Metastatic Disease; Hepatocellular Carcinoma (HCC); Radiotherapy; Systemic Therapy

Keywords

oligoprogressive; HCC; radiotherapy; first-line systemic therapy

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS)

  The time between enrollment and disease progression or death for patients in the intent-to-treat population, whichever occurred first; for those who did not progress at the time of withdrawal from the study or whose time to disease progression was not recorded, the date of the last visit was used as the endpoint date.

  2 years

Secondary Outcomes (5)

• Overall survival (OS)

  5 years

• Adverse event incidence (Safety)

  2 years

• Objective response rate (ORR)

  2 years

• Disease control rate (DCR)

  2 years

• Duration of response (DOR)

  2 years

Study Arms (2)

Radiotherapy group

EXPERIMENTAL

Patients will continue their current first-line systemic treatment, which may include, but is not limited to, combinations such as atezolizumab plus bevacizumab, tremelimumab plus durvalumab, or monotherapies such as lenvatinib, sorafenib, tislelizumab, durvalumab, or pembrolizumab, at the discretion of the treating physician. All oligoprogressive lesions will receive radiotherapy. Radiotherapy Techniques: 3D-CRT, IMRT, IGRT. Radiation dose and fractionation: radiation dose will be biologically effective dose (BED) ≥60 Gy, adjusted based on tumor location and size. For intrahepatic oligoprogressive lesions, eligibility for radiotherapy is determined by multidisciplinary team (MDT) consultation, and patients must meet the following criteria 1. Residual normal liver volume ≥700 mL 2. D ≥ 700 cc ≤ 23 Gy (for Child-Pugh B patients) If oligoprogression recurs after ≥3 months, additional radiotherapy will be administered in addition to continuation of current first-line systemic therapy.

Radiation: radiotherapy; Drug: Systemic therapy (Continuation of current first-line systemic therapy)

Control

ACTIVE COMPARATOR

For patients who received sorafenib as FLST, regorafenib will be the preferred second-line option. For patients who received other FLST regimens, the SLST selection will be determined through an MDT discussion led by the treating physician based on the patient's overall condition, prior therapies, drug indications, and potential adverse effects, ensuring an individualized treatment approach. The specific dosing regimen, administration frequency, and dose adjustments will strictly follow the same prescribing information for each drug.

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

Interventions

radiotherapy RADIATION

Radiotherapy (Biologically Equivalent Dose \[BED\]≥60Gy)

Also known as: RT

Radiotherapy group

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

Continuation of current first-line systemic therapy, which may include, but is not limited to, combinations such as atezolizumab plus bevacizumab, tremelimumab plus durvalumab, or monotherapies such as lenvatinib, sorafenib, tislelizumab, durvalumab, or pembrolizumab, at the discretion of the treating physician.

Also known as: c-FLST

Radiotherapy group

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

For patients who received sorafenib as FLST, regorafenib will be the preferred second-line option. For patients who received other FLST regimens, the SLST selection will be determined through an MDT discussion led by the treating physician based on the patient's overall condition, prior therapies, drug indications, and potential adverse effects, ensuring an individualized treatment approach. The specific dosing regimen, administration frequency, and dose adjustments will strictly follow the same prescribing information for each drug.

Also known as: s-SLST

Control

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Histological or cytological confirmation of primary hepatocellular carcinoma (HCC), or diagnosis based on the Clinical Diagnosis and Treatment Guidelines for Primary Liver Cancer (2024 edition) issued by the National Health Commission of the People's Republic of China.
• \. BCLC stage C at the time of first-line systemic treatment.
• \. Oligoprogression must be confirmed by imaging or histopathology during first-line systemic therapy (FLST). The number of oligoprogressive lesions is limited to 1-5, involving no more than 1-3 organs or systems. These lesions may represent either new metastatic sites or progression of pre-existing lesions. In addition, they must fit one of the two classifications defined in the ESTRO-EORTC consensus on oligometastases: repeat oligoprogression or induced oligoprogression. Oligoprogression may occur within intrahepatic lesions. In the case of lymph node progression, each lymphatic drainage region is considered a separate lesion. For example, the para-aortic lymph nodes (number 16a and number 16b) are each counted as separate lymph node regions.
• \. Patients must have experienced oligoprogression while receiving their current FLST and must not have previously received any other FLST that resulted in disease progression. Additionally, the current FLST must have maintained disease stability (SD) for at least three months prior to the occurrence of oligoprogression. Furthermore, the expected survival time must be ≥6 months.
• \. Oligoprogressive lesions must be eligible for radiotherapy and should have at least one measurable lesion that meets RECIST v1.1 criteria; Bone metastases without soft tissue formation are eligible but are considered non-measurable lesions; Bone metastases with soft tissue formation that meet RECIST v1.1 measurable criteria are considered measurable lesions.
• \. Liver function must be assessed as Child-Pugh score ≤7 points.
• \. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0-1.
• \. Participants must be able to understand and voluntarily sign a written informed consent prior to the initiation of any study-specific procedures and must agree to comply with the treatment and follow-up requirements of the study.
• \. Male or female patients between 18 and 75 years of age.
• \. Availability of tumor and blood samples for biomarker assessment.

You may not qualify if:

• \. Patients who received FLST as adjuvant treatment after curative surgery for HCC.
• \. Tumor progression occurring within 3 months after initiation of FLST.
• \. Patients with combined hepatocellular-cholangiocarcinoma (cHCC-CC)
• \. History of grade ≥3 serious adverse events due to FLST.
• \. Presence of brain, peritoneal or omental metastases with bleeding after FLST.
• \. Previous radiation therapy to the site of the oligoprogressive lesion.
• \. Active untreated hepatitis B, defined as HBsAg positive with HBV DNA levels above the upper limit of normal in the participating center's laboratory.
• \. Oligoprogressive lesions not amenable to radiotherapy.
• \. Alpha-fetoprotein (AFP) level ≥10,000 ng/mL at the time of oligoprogression.
• \. Diagnosis of malignancy other than liver cancer within 3 years prior to enrollment (excluding curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, and/or carcinoma in situ).
• \. Currently participating in any interventional clinical research treatment or having received any other investigational drug or investigational device therapy within the last 4 weeks prior to enrollment.
• \. Presence of autoimmune disease or other conditions requiring long-term steroid use.
• \. Severe impairment of the heart, lungs, kidneys, or other vital organs, active infections (other than viral hepatitis), or other serious comorbidities that render the patient unable to tolerate treatment.
• \. known or suspected allergy to any study drug or to any drug related to this study.
• \. History of organ transplantation

Sponsors & Collaborators

• Shandong Cancer Hospital and Institute: lead

Study Sites (1)

Jinan, Shandong 0531

Jinan, Shandong, China

RECRUITING

Related Publications (8)

• Leng B, Wang H, Ge Y, Sun X, Dong P, Dong X, Duan X, Wang Q, Xia Y, Ding L, Dai H, Liu T, Shi F, Zhang X, Yue J. Maintaining First-Line Therapy Plus Radiation Therapy May Prolong Progression-Free Survival and Delay Second-Line Therapy for Oligoprogressive Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys. 2025 Jun 1;122(2):325-338. doi: 10.1016/j.ijrobp.2024.12.039. Epub 2025 Jan 15.

  PMID: 39824367 BACKGROUND

• Choi SH, Lee BM, Kim J, Kim DY, Seong J. Efficacy of stereotactic ablative radiotherapy in patients with oligometastatic hepatocellular carcinoma: A phase II study. J Hepatol. 2024 Jul;81(1):84-92. doi: 10.1016/j.jhep.2024.03.003. Epub 2024 Mar 11.

  PMID: 38467379 BACKGROUND

• Doyle E, Killean AJ, Harrow S, Phillips ID. Systematic review of the efficacy of stereotactic ablative radiotherapy for oligoprogressive disease in metastatic cancer. Radiother Oncol. 2024 Jul;196:110288. doi: 10.1016/j.radonc.2024.110288. Epub 2024 Apr 20.

  PMID: 38648995 BACKGROUND

• Tan VS, Padayachee J, Rodrigues GB, Navarro I, Shah PS, Palma DA, Barry A, Fazelzad R, Raphael J, Helou J. Stereotactic ablative radiotherapy for oligoprogressive solid tumours: A systematic review and meta-analysis. Radiother Oncol. 2024 Nov;200:110505. doi: 10.1016/j.radonc.2024.110505. Epub 2024 Aug 26.

  PMID: 39197501 BACKGROUND

• Wang Q, Yu J, Sun X, Li J, Cao S, Han Y, Wang H, Yang Z, Li J, Hu C, Zhang Y, Jin L. Sequencing of systemic therapy in unresectable hepatocellular carcinoma: A systematic review and Bayesian network meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol. 2024 Dec;204:104522. doi: 10.1016/j.critrevonc.2024.104522. Epub 2024 Sep 26.

  PMID: 39332750 BACKGROUND

• Cappuyns S, Corbett V, Yarchoan M, Finn RS, Llovet JM. Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma: A Review. JAMA Oncol. 2024 Mar 1;10(3):395-404. doi: 10.1001/jamaoncol.2023.2677.

  PMID: 37535375 BACKGROUND

• Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, Pikarsky E, Zhu AX, Finn RS. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022 Mar;19(3):151-172. doi: 10.1038/s41571-021-00573-2. Epub 2021 Nov 11.

  PMID: 34764464 BACKGROUND

• Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013 Nov;19(11):1423-37. doi: 10.1038/nm.3394.

  PMID: 24202395 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Radiotherapy

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Jinbo Yue, Doctor

  Shandong Cancer Hospital and Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jinbo Yue, Doctor

CONTACT

0531-67626442; jbyue@sdfmu.edu.cn

Jinbo Yue, Doctor

CONTACT

jbyue@sdfmu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Radiation Oncology Department

Study Record Dates

• First Submitted: February 18, 2025
• First Posted: February 24, 2025
• Study Start: July 21, 2025
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2028
• Last Updated: August 1, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)