Hepatocellular Carcinoma (HCC)
Conditions
Keywords
SBRT, bevacizumab, immunotherapy, oligometastatic
Brief summary
SBRT combined with dual PD-1/CTLA-4 blockade (iparomlimab and tuvonralimab, QL1706) and bevacizumab may provide complementary local and systemic antitumor activity in hepatocellular carcinoma (HCC). This prospective, single-arm, single-center study evaluates the efficacy and safety of stereotactic body radiotherapy (SBRT) to all intra- and extrahepatic lesions combined with QL1706 (7.5 mg/kg intravenously on day 1 every 3 weeks) and bevacizumab (15 mg/kg intravenously on day 1 every 3 weeks) in patients with inoperable locally advanced or oligometastatic HCC (BCLC stage B or C). All lesions receive SBRT at 8 Gy in 3-5 fractions completed within 30 days; systemic therapy starts within 1 week before or after the start of radiotherapy and continues as maintenance for up to 2 years, until progression, death, or unacceptable toxicity. The primary endpoint is objective response rate per RECIST 1.1. Secondary endpoints include complete response, disease control rate, time to response, duration of response, local control, progression-free survival, time to progression, and overall survival per RECIST 1.1 and mRECIST, safety per CTCAE v6.0, and quality of life per EORTC QLQ-C30 and QLQ-HCC18. A total of 33 patients will be enrolled at Beijing Cancer Hospital.
Detailed description
Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Immune checkpoint inhibition combined with anti-angiogenic therapy is the standard first-line systemic treatment for unresectable HCC, but outcomes remain suboptimal. Radiotherapy is not only an effective local treatment but also a potent immunomodulator; stereotactic body radiotherapy (SBRT) can induce immunogenic cell death, promote type I interferon and damage-associated molecular pattern release, and prime antitumor T-cell responses, providing a rationale for combining SBRT with dual PD-1/CTLA-4 blockade and anti-VEGF therapy. No prospective evidence currently exists for SBRT combined with dual immunotherapy plus anti-angiogenic therapy in unresectable HCC. Objective: To evaluate the efficacy and safety of SBRT combined with iparomlimab and tuvonralimab (QL1706, a bifunctional PD-1/CTLA-4 antibody) and bevacizumab in patients with inoperable locally advanced or oligometastatic HCC. Design: Prospective, single-arm, single-center, exploratory interventional study at Beijing Cancer Hospital. Enrollment period: 24 months; estimated 33 participants. Eligibility: adults (\>=18 years) with imaging- or pathology-proven, inoperable BCLC stage B or C HCC unsuitable for surgery, ablation, or transarterial therapy, either locally advanced (portal/hepatic/inferior vena cava tumor thrombus permitted) or oligometastatic (up to 5 extrahepatic lesions); no prior systemic therapy or progression/intolerance after first-line therapy; ECOG 0-1; Child-Pugh A or B (score \<=7); Child-Pugh class, laboratory thresholds, and the full inclusion and exclusion criteria are listed in the Eligibility module. Interventions: All intra- and extrahepatic lesions receive SBRT with a prescription of 8 Gy x 3-5 fractions (fraction number determined by lesion location and proximity to organs at risk), one fraction per day or every other day on weekdays, with all treatment completed within 30 days and interfraction intervals of 24-72 hours; image-guided radiotherapy is used at every fraction. QL1706 7.5 mg/kg and bevacizumab 15 mg/kg are given intravenously on day 1 of each 21-day cycle, starting within 1 week before or after the start of SBRT; after the combined-treatment phase, both drugs continue as maintenance until 2 years of cumulative systemic treatment, disease progression, death, or unacceptable toxicity. Outcome measures and statistical analysis: The outcome measures are listed in the Outcome Measures module; in brief, the primary endpoint is objective response rate per RECIST 1.1, with response assessed by investigators on the first imaging assessment 4-6 weeks after SBRT and every 12 weeks thereafter. Time-to-event endpoints are estimated with the Kaplan-Meier method. Efficacy is analyzed in all patients receiving at least one dose of study treatment or radiotherapy; safety (CTCAE v6.0) is analyzed in all patients receiving any study treatment. All analyses are two-sided with alpha = 0.05. Exploratory translational studies use blood (genetic sequencing, immune-related factors, plasma PD-1/PD-L1, T-cell receptor repertoire) and stool (metabolomics, metagenomics) specimens collected before the first dose, after completion of radiotherapy, and at progression.
Interventions
RADIATIONStereotactic Body Radiotherapy
SBRT to all intra- and extrahepatic lesions. Prescription dose 8 Gy x 3-5 fractions, with the fraction number determined by lesion location and proximity to organs at risk; one fraction per day or every other day on weekdays; interfraction interval 24-72 hours; the entire course completed within 30 days; image-guided radiotherapy at every fraction.
DRUGBevacizumab
Bevacizumab injection. 15 mg/kg intravenous infusion on day 1 of each 21-day cycle, on the same schedule as QL1706, continued as maintenance until 2 years of cumulative treatment, disease progression, death, or unacceptable toxicity.
QL1706 (commercial name Qibeian), a bifunctional anti-PD-1/CTLA-4 combination antibody. 7.5 mg/kg intravenous infusion on day 1 of each 21-day cycle, starting within 1 week before or after the start of SBRT and continued as maintenance until 2 years of cumulative treatment, disease progression, death, or unacceptable toxicity.
Sponsors
Peking University Cancer Hospital & Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \>= 18 years, male or female. 2. Histologically or radiologically confirmed hepatocellular carcinoma. 3. Barcelona Clinic Liver Cancer (BCLC) stage B or C. 4. Inoperable disease, not a transplant candidate, and unsuitable for ablation or transarterial therapy, including locally advanced and oligometastatic disease. 4.1 Locally advanced: no extrahepatic metastasis; portal vein, hepatic vein, or inferior vena cava tumor thrombus permitted. 4.2 Oligometastatic: a limited number (\<=5) of extrahepatic metastatic lesions (lymph node, visceral, bone, adrenal, or soft tissue; brain metastases excluded), with or without intrahepatic disease meeting the locally advanced definition. Vascular invasion is not counted in the lesion number, and lesions achieving complete response (per RECIST 1.1) after prior therapy are not counted. 5. At least one measurable lesion per RECIST 1.1. 6. All lesions can safely receive stereotactic body radiotherapy. 7. No prior systemic therapy, or progression or intolerance after first-line systemic therapy, with more than 3 weeks since the last dose. 8. ECOG performance status 0-1 within 1 week before enrollment. 9. Child-Pugh class A or B (score \<=7). 10. Hematology: hemoglobin \>=90 g/L; white blood cell count \>=3.0 x 10\^9/L; absolute neutrophil count \>=1.5 x 10\^9/L; platelet count \>=75 x 10\^9/L. 11. INR \<=2.3, or prothrombin time exceeding the upper limit of normal by \<=6 seconds. 12. ALT and AST \<=5 x upper limit of normal (ULN); alkaline phosphatase \<=5 x ULN; total bilirubin \<=3 x ULN; albumin \>=28 g/L. 13. Serum creatinine \<=1.5 x ULN, or creatinine clearance \>=50 mL/min calculated by the Cockcroft-Gault formula. 14. Urine protein \<2+ (patients with urine protein \>=2+ may undergo 24-hour urine protein quantification and are eligible if the 24-hour urine protein is \<1.0 g). 15. Patients with active hepatitis B virus (HBV) infection: HBV-DNA \<500 IU/mL (or \<2500 copies/mL if only copy/mL is available) and willingness to receive antiviral therapy throughout the study; patients positive for hepatitis C virus (HCV) RNA must receive standard antiviral therapy, with hepatic enzyme elevation \<=CTCAE grade 1. 16. Women of childbearing potential (generally 15-49 years) must have a negative serum or urine pregnancy test within 14 days before enrollment and be willing to use adequate contraception during the study and for 8 weeks after the last dose of study drug; men must be surgically sterile or agree to adequate contraception during the study and for 8 weeks after the last dose. 17. Voluntary participation with signed informed consent, good compliance, and willingness to undergo follow-up.
Exclusion criteria
1. Age \<18 years. 2. ECOG performance status \>=2. 3. Poor liver function: Child-Pugh score \>7, or hepatic enzymes, coagulation, bilirubin, or bone marrow function not meeting the enrollment criteria. 4. Hepatic encephalopathy, massive ascites, or abdominal infection within 1 month. 5. Brain metastases. 6. Malignant pleural effusion. 7. Prior radiotherapy to any site requiring treatment in this study (risk of field overlap causing excessive irradiation of normal tissue). 8. Prior selective internal radiation therapy or yttrium-90 hepatic arterial therapy. 9. Tumor directly invading the stomach, duodenum, small intestine, or large intestine; or tumor within 3 mm of the spinal cord. 10. Maximum diameter of any single lesion \>15 cm. 11. Sum of the maximum diameters of all intrahepatic lesions, or the maximum diameter of a single confluent lesion, \>20 cm. 12. More than 5 discrete intrahepatic HCC lesions. 13. Normal liver volume \<700 mL. 14. Known history of allogeneic organ or hematopoietic stem cell transplantation, or planned transplantation. 15. Known allergy to iparomlimab and tuvonralimab, bevacizumab, or drug excipients, or severe hypersensitivity to any other monoclonal antibody. 16. Live attenuated vaccination within 4 weeks before the first dose or planned during the study. 17. Severe active autoimmune disease. 18. Any other malignancy, except adequately treated basal cell or squamous cell skin carcinoma or cervical carcinoma in situ. 19. Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS). 20. Within 6 months before enrollment: myocardial infarction, severe or unstable angina, NYHA class \>=2 heart failure, poorly controlled arrhythmia, or symptomatic congestive heart failure. 21. Coagulation abnormality with bleeding tendency, or currently receiving thrombolytic, anticoagulant, or antiplatelet therapy. 22. Known hereditary or acquired bleeding or thrombotic tendency, such as hemophilia, coagulation disorders, or severe thrombocytopenia. 23. Risk of gastrointestinal bleeding, including: (1) active peptic ulcer; (2) melena or hematemesis within 1 month; (3) gastroscopy showing ulcer or bleeding lesions, esophagogastric varices with red color signs (+), or variceal diameter \>1 cm. Also: history of psychotropic drug abuse or drug addiction, or other severe medical or psychiatric illness, or laboratory abnormality that may increase study risk, confound results, or render the patient unsuitable in the investigator's judgment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate per RECIST 1.1 | From the first imaging assessment performed 4-6 weeks after completion of SBRT, repeated every 12 weeks until progression, death, or completion of 2-year follow-up | Proportion of patients achieving complete response or partial response per RECIST 1.1, assessed by investigators. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) per RECIST 1.1 | From the first imaging assessment performed 4-6 weeks after completion of SBRT, repeated every 12 weeks until progression, death, or completion of 2-year follow-up | Proportion of patients achieving complete response (disappearance of all target lesions) per RECIST 1.1, assessed by investigators. |
| Disease Control Rate (DCR) per RECIST 1.1 | From the first imaging assessment performed 4-6 weeks after completion of SBRT, repeated every 12 weeks until progression, death, or completion of 2-year follow-up | Proportion of patients achieving complete response, partial response, or stable disease (CR + PR + SD) per RECIST 1.1, assessed by investigators. |
| Time to Response (TOR) | From enrollment to the first documented response (RECIST 1.1 and mRECIST), up to 2 years | Time from enrollment to the first documented tumor response per RECIST 1.1 and mRECIST. |
| Duration of Response (DOR) | From first documented response to disease progression or death from any cause, up to 2 years | Time from first documented response until disease progression or death from any cause, per RECIST 1.1 and mRECIST. |
| Local Control (LC) | From enrollment to first progression within the irradiated volume (within the 80% isodose line), assessed every 12 weeks, up to 2 years | Time from enrollment to first progression within the high-dose irradiated region (within the 80% isodose line), per RECIST 1.1 and mRECIST. |
| Progression-Free Survival (PFS) | From enrollment to disease progression or death from any cause, up to 2 years | Time from enrollment to disease progression or death from any cause, per RECIST 1.1 and mRECIST. |
| Time to Progression (TTP) | From enrollment to disease progression, up to 2 years | Time from enrollment to disease progression, per RECIST 1.1 and mRECIST. |
| Overall Survival (OS) | From enrollment to death from any cause, up to 2 years of follow-up | Time from enrollment until death from any cause. |
| Incidence of Adverse Events | From first dose of study treatment until 30 days after the last dose for adverse events and serious adverse events; safety follow-up visit 6 weeks after the last dose | Incidence, severity (CTCAE v6.0), relatedness, and outcome of adverse events and serious adverse events, including incidence of grade 3 or higher events, treatment-related events, fatal events, and events leading to treatment discontinuation. |
| Composite of Quality of Life by EORTC QLQ-C30 and QLQ-HCC18 | At baseline, every 1-2 weeks during radiotherapy, and at each treatment cycle until the end of treatment, up to 2 years | Quality of life assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30, version 3.0; 30 items) and its hepatocellular carcinoma-specific supplemental module (EORTC QLQ-HCC18; 18 items). All scale scores are transformed linearly to a range from 0 to 100; a higher score represents a better outcome for the global health status and functional scales, and a worse outcome for the symptom scales. Scores are calculated per the official EORTC scoring manual. |
| Objective Response Rate (ORR) per mRECIST | From the first imaging assessment performed 4-6 weeks after completion of SBRT, repeated every 12 weeks until progression, death, or completion of 2-year follow-up | Proportion of patients achieving complete response or partial response (CR + PR) per modified RECIST (mRECIST), assessed by investigators. |
| Complete Response (CR) per mRECIST | From the first imaging assessment performed 4-6 weeks after completion of SBRT, repeated every 12 weeks until progression, death, or completion of 2-year follow-up | Proportion of patients achieving complete response per modified RECIST (mRECIST), assessed by investigators. |
| Disease Control Rate (DCR) per mRECIST | From the first imaging assessment performed 4-6 weeks after completion of SBRT, repeated every 12 weeks until progression, death, or completion of 2-year follow-up | Proportion of patients achieving complete response, partial response, or stable disease (CR + PR + SD) per modified RECIST (mRECIST), assessed by investigators. |
Countries
China
Contacts
CONTACTXuan Zheng, MD
PRINCIPAL_INVESTIGATORWeihu Wang, MD
Peking University Cancer Hospital & Institute
Outcome results
None listed