Combination of SBRT, PD-L1 Inhibitor, and Lenvatinib in Hepatocellular Carcinoma (HSBRT2401)

Hepatocellular Carcinoma Clinical Trial

— HSBRT2401  

Official title:

Efficacy and Safety of Stereotactic Body Radiotherapy Followed by Adebrelimab and Lenvatinib for Hepatocellular Carcinoma With Abdominal Lymph Node Metastases: A Two-arm, Phase II Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06261125
• Other study ID #: SL-B2023-718
• Status: Recruiting
• Phase: Phase 2
• Start date: March 10, 2024
• Est. completion date: June 30, 2028

Study information

• Verified date: March 2024
• Source: Sun Yat-sen University
• Contact: Mian Xi, MD
• Phone: +862087343385
• Email: ximian[@]sysucc.org.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Abdominal lymph node metastasis (LNM) is one of the major modes of extrahepatic metastasis in hepatocellular carcinoma (HCC). Immunotherapy targeting the PD-1/PD-L1 checkpoints combined with targeted therapy is the standard treatment for HCC with abdominal LNM, but the outcome remains very poor, with an objective response rate of 5% to 30%. Previous studies have demonstrated that stereotactic body radiotherapy (SBRT) is an effective local treatment for HCC with abdominal LNM, with a high response rate of 60% to 80%. However, intrahepatic dissemination and distant metastasis remains the major recurrence pattern after SBRT in these patients, suggesting radiotherapy should be combined with systematic treatment. Recently, the combination of immunotherapy with SBRT has shown promising activity in HCC. The aim of this study was to investigate the efficacy and safety of SBRT followed by adebrelimab (an anti-PD-L1 antibody) and lenvatinib in HCC patients with portal abdominal LNM.

Description:

A total of 60 HCC patients (2 cohorts) with abdominal LNM will be enrolled to receive SBRT followed by adebrelimab (an anti-PD-L1 antibody) and lenvatinib. Arm A included the patients who previously had not received PD-1/PD-L1 antibody, and Arm B included the patients who had progressed after receiving PD-1/PD-L1 antibody. Patients in both cohorts will receive stereotactic body radiotherapy (SBRT) using volumetric arc therapy. The prescribed dose is 33-48 Gy in 6 fractions over 2 weeks. Then all patients will receive lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) orally once daily in combination with adebrelimab 1200 mg every 3 weeks for up to 35 cycles. The first course of adebrelimab will be given within 1 week after completion of SBRT.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: June 30, 2028
• Est. primary completion date: June 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Histologically confirmed hepatocellular carcinoma or diagnosed by American Association for the Study of Liver Disease criteria;

2. Presence of abdominal metastatic lymph nodes confirmed by CT or MRI, the sum of the maximum diameter of lymph nodes =10 cm, and at least one of which is measurable according to the RECIST 1.1 Criteria;

3. Previous local treatment for intrahepatic lesion and systemic anti-tumor therapy are allowed; no matter whether the disease progressed or not;

4. Less than 3 active intrahepatic lesions with a total diameter of less than 10 cm; Portal vein invasion is allowed; absence of other extrahepatic metastasis disease except abdominal LNM;

5. Cohort 1: Patients who never received PD-1/PD-L1 antibody therapy; Cohort 2: patients who had tumor progression after previous PD-1/PD-L1 antibody therapy.

6. Age at diagnosis 18 to 75 years;

7. Eastern Cooperative Oncology Group performance status = 2

8. Child-Pugh class A liver function;

9. Normal liver volume greater than 700 ml;

10. Estimated life expectancy =12 weeks;

11. The function of important organs meets the following requirements: a. white blood cell count (WBC) = 3.0×109/L, absolute neutrophil count (ANC) = 1.5×109/L; b. platelets = 50×109/L; c. hemoglobin = 9g/dL; d. serum albumin = 2.8g/dL; e. total bilirubin = 1.5×ULN, ALT, AST and/or AKP = 2.5×ULN; f. serum creatinine = 1.5×ULN or creatinine clearance rate >60 mL/min;

12. Ability to understand the study and sign informed consent.

Exclusion Criteria:

1. Diffuse hepatocellular carcinoma;

2. Patients who have previously been treated with lenvatinib or PD-1/PD-L1 antibody but could not be tolerated;

3. Patients with other extrahepatic metastasis disease except abdominal LNM;

4. A history of abdominal radiotherapy;

5. Known or suspected allergy or hypersensitivity to monoclonal antibodies;

6. Patients who have a preexisting or coexisting bleeding disorder;

7. Female patients who are pregnant or lactating;

8. Inability to provide informed consent due to psychological, familial, social and other factors;

9. A history of malignancies other than hepatocellular carcinoma before enrollment, excluding non-melanoma skin cancer, in situ cervical cancer, or cured early prostate cancer;

10. A history of diabetes for more than 10 years and poorly controlled blood glucose levels;

11. Patients who cannot tolerate radiotherapy due to severe cardiac, lung, liver or kidney dysfunction, or hematopoietic disease or cachexia;

12. Active autoimmune diseases, a history of autoimmune diseases (including but not limited to these diseases or syndromes, such as colitis, hepatitis, hyperthyroidism), a history of immunodeficiency (including a positive HIV test result), or other acquired or congenital immunodeficiency diseases, a history of organ transplantation or allogeneic bone marrow transplantation;

13. A history of interstitial lung disease or non-infectious pneumonia;

14. A history of active pulmonary tuberculosis infection within 1 year or a history of active pulmonary tuberculosis infection more than 1 year ago but without formal anti-tuberculosis treatment;

15. Presence of active hepatitis B (HBV DNA = 2000 IU/mL or 104 copies/mL), hepatitis C (positive for hepatitis C antibody, and HCV-RNA levels higher than the lower limit of the assay);

16. Any unstable situation that may endanger the safety and compliance of patients.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Radiation:
• Stereotactic body radiotherapy
Patients in both cohorts will receive stereotactic body radiotherapy (SBRT) using volumetric arc therapy. The prescribed dose is 33-48 Gy in 6 fractions over 2 weeks.

Drug:
• Adebrelimab
All patients will reveive adebrelimab 1200 mg every 3 weeks for up to 35 cycles after the completion of SBRT.
• Lenvatinib
All patients will receive lenvatinib (12 mg/day for bodyweight =60 kg or 8 mg/day for bodyweight <60 kg) orally once daily after the completion of SBRT.

Locations

Country	Name	City	State
China	Mian Xi	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Mian XI

Country where clinical trial is conducted

China, 

References & Publications (4)

Chiang CL, Chiu KWH, Chan KSK, Lee FAS, Li JCB, Wan CWS, Dai WC, Lam TC, Chen W, Wong NSM, Cheung ALY, Lee VWY, Lau VWH, El Helali A, Man K, Kong FMS, Lo CM, Chan AC. Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed b — View Citation

Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, Okusaka T, Kobayashi M, Kumada H, Kaneko S, Pracht M, Mamontov K, Meyer T, Kubota T, Dutcus CE, Saito K, Siegel AB, Dubrovsky L, Mody K, Llovet JM. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Pat — View Citation

Kim HJ, Park S, Kim KJ, Seong J. Clinical significance of soluble programmed cell death ligand-1 (sPD-L1) in hepatocellular carcinoma patients treated with radiotherapy. Radiother Oncol. 2018 Oct;129(1):130-135. doi: 10.1016/j.radonc.2017.11.027. Epub 201 — View Citation

Wang Y, Li Q, Zhang L, Liu S, Zhu J, Yang Y, Liu M, Zhang Y, Xi M. Efficacy and Dose-Response Relationship of Stereotactic Body Radiotherapy for Abdominal Lymph Node Metastases from Hepatocellular Carcinoma. Oncologist. 2023 Jun 2;28(6):e369-e378. doi: 10 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Correlation between serum cytokines and overall survival and immune-related adverse events	The correlation between dynamic change of serum cytokines (IL-2R, IL-6, IL-13, IL-8, CCL3, CD40, and CD274) during treatment and survival outcomes and immune-related adverse events.	From date of enrollment to the date of last follow-up, assessed up to 36 months.
Primary	Progression-free survival (PFS)	Three-year follow-up from the date of enrollment to the date of disease progression or last follow-up	From date of enrollment until the date of death from any cause or the date of first documented disease progression whichever came first, assessed up to 36 months.
Secondary	Overall survival (OS)	Three-year follow-up from the enrollment to the date of death from any cause or date of lost follow-up	From date of enrollment until the date of death from any cause or the date of last follow-up, whichever came first, assessed up to 36 months.
Secondary	Overall response rate (ORR)	Tumor response was evaluated every 9 weeks after the completion of radiotherapy based on CT or MRI scan.	From date of enrollment to the date of last follow-up, assessed up to 36 months.
Secondary	Disease control rate (DCR)	The proportion of patients with complete response, partial response, or stable disease according to RECIST criteria.	From date of enrollment to the date of last follow-up, assessed up to 36 months.
Secondary	Duration of response (DOR)	From the date of first CR/PR to the date of first PD.	From date of first CR/PR to the date of first PD according to RECIST criteria, assessed up to 36 months.
Secondary	Treatment-related adverse events	Incidence of treatment-related adverse events as assessed by CTCAE v4.0.	From date of enrollment to the date of last follow-up, assessed up to 36 months.