Combination of SFRT, PD-L1 Inhibitor, and Anti-VEGF in Advanced Hepatocellular Carcinoma

A Single-arm, Single-center, Open-label Study to Evaluate the Efficacy and Safety of SFRT Combined With PD-1 Inhibitors and Anti-VEGFR in Unresectable Hepatocellular Carcinoma

PD-1 inhibitor plus anti-VEGFR has become the established standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Despite an improved objective response rate (ORR) of around 30%, the majority of patients face HCC progression and liver failure. Developing a new combined treatment strategy to overcome resistance to anti-PD-L1 and anti-VEGF is essential to improve patient outcomes. Stereotactic radiotherapy (SBRT) can enhance immune response through various mechanisms, and its immunomodulatory effect has been confirmed in multiple solid tumors. However, due to the limitation of the OAR tolerance dose, large-volume tumors are unsuitable for SBRT treatment. To overcome this issue, researchers have introduced the spatially fractionated radiation therapy (SFRT) mode, which allows for a highly uneven radiation dose distribution within the tumor volume. SFRT is an emerging radiotherapy technique with high clinical response rates and low radiation-related toxicity in large-volume solid tumors. Therefore, the investigators conducted this single-arm, single-arm, open-label study to evaluate the efficacy and safety of SFRT combined with PD-1 inhibitors and anti-VEGFR in unresectable HCC. The primary endpoint is objective response rate (ORR), and secondary endpoints include overall survival (OS), progression-free survival (PFS), and toxicity.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatocellular Carcinoma; Radiotherapy; PD-1 Inhibitors
• Intervention / Treatment: Radiation: Combination of SFRT, PD-L1 inhibitor, and Anti-VEGF

Detailed Description

This is a single-arm, single-center, open-label study to evaluate the efficacy and safety of SFRT combined with PD-1 inhibitors (Camrelizumab, Tislelizumab or Sintilimab) and anti-VEGFR (Apatinib or Lenvatinib) in unresectable HCC. Patients received intravenous PD-1 inhibitor 200mg(Camrelizumab, Tislelizumab, or Sintilimab) plus oral Apatinib 250 mg or Lenvatinib 12mg (for bodyweight ≥60 kg) or 8 mg/kg (for bodyweight <60 kg) daily, and additional SFRT for primary liver tumor. PD-1 inhibitor is administered for 2 years or until disease progression or intolerance. Anti-VEGFR is continued until disease progression or intolerance. SFRT implementation plan is as follows: The GTV consists of 2-5 sub-target volumes, which are cylindrical shapes with a diameter of 1.6cm, a height of 2cm, and an interval of 3-5cm. The total volume of the GTV is about 8-20cc, and the distance between the GTV and the OARs is greater than 2cm. The prescribed dosage for each course of radiotherapy is 24 Gy in 3 daily fractions (8Gy x 3F), with a 3-week interval between courses (Q3W). The total courses of radiotherapy shall not be less than 2 (depending on the efficacy and cumulative dose of OARs). The primary endpoint is objective response rate (ORR), and secondary endpoints include overall survival (OS), progression-free survival (PFS), and toxicity.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yaocan Xu, MD; Phone Number: 86+17376359808; Email: gxmuxyc@163.com

Study Locations

• China
  • Guangxi
    • Guiping, Guangxi, China, 537200
      • Guiping People's Hospital
      • Contact: Yaocan Xu, MD; Phone Number: 86+17376359808; Email: gxmuxyc@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age: 18-75 years old;
2. Eastern Cooperative Oncology Group (ECOG) -Performance Status(PS):0-1 points；
3. Patient clinically or pathologically diagnosed with hepatocellular carcinoma；
4. Advanced hepatocellular carcinoma that is inoperable
5. Expected survival period≥3 months;
6. Liver function grade Child-Pugh A or better grade B (7 points);

Exclusion Criteria:

1. Prior invasive malignancy unless disease-free for a minimum of 2 years
2. Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields
3. Prior selective internal radiotherapy/ablation, at any time
4. Untreated active hepatitis B or hepatitis C
5. Moderate to severe or intractable ascites
6. Untreated or incompletely treated esophageal or gastric varices

7. Severe, active co-morbidity, defined as follows:

   Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to registration Myocardial infarction within the last 6 months prior to study entry Acute bacterial or fungal infection requiring intravenous antibiotics within 28 days prior to study entry A bleeding episode within 6 months prior to study entry due to any cause. Thrombolytic therapy within 28 days prior to study entry. Known bleeding or clotting disorder. Uncontrolled psychotic disorder

8. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
9. Prior solid organ transplantation.
10. Immunodeficiency diseases (including HIV) or autoimmune diseases require systemic immunosuppressive therapy (prednisone dosage>10mg per day)
11. Prior or active thrombotic or bleeding disorders, hemoptysis, cerebral vascular accident, significant cardiac disease (ischemic or congestive heart failure), or gastrointestinal perforation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Combination of SFRT, PD-L1 inhibitor, and Anti-VEGF in Advanced Hepatocellular Carcinoma

Radiation: Combination of SFRT, PD-L1 inhibitor, and Anti-VEGF; Patients received intravenous PD-1 inhibitor 200mg(Camrelizumab, Tislelizumab, or Sintilimab) plus oral Apatinib 250 mg or Lenvatinib 12mg (for bodyweight ≥60 kg) or 8 mg/kg (for bodyweight <60 kg) daily, and additional SFRT for primary liver tumor. PD-1 inhibitor is administered for 2 years or until disease progression or intolerance. Anti-VEGFR is continued until disease progression or intolerance. SFRT implementation plan is as follows: The GTV consists of 2-5 sub-target volumes, which are cylindrical shapes with a diameter of 1.6cm, a height of 2cm, and an interval of 3-5cm. The total volume of the GTV is about 8-20cc, and the distance between the GTV and the OARs is greater than 2cm. The prescribed dosage for each course of radiotherapy is 24 Gy in 3 daily fractions (8Gy x 3F), with a 3-week interval between courses (Q3W). The total courses of radiotherapy shall not be less than 2 (depending on the efficacy and cumulative dose of OARs).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
objective response rate (ORR)	Objective response rate will be ratepresented as a proportion of the total.	36 months after registration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Progression-free survival and overall survival are evaluated using the Kaplan-Meier curve. Verified through one sample proportion test.	36 months after registration
Adverse event (Toxicity)	Toxicity will be evaluated using CTCAE version 5.0 and presented as a proportion of the total.	36 months after registration
Progression-free survival	Progression-free survival and overall survival are evaluated using the Kaplan-Meier curve. Verified through one sample proportion test.	36 months after registration
Tumor marker response: AFP	Tumor marker is descriptive as statistics such as mean, standard deviation, and median for continuous data will be presented, and changes in values before and after treatment will be compared and evaluated using paired t-test or Wilcoxon signed rank test.	36 months after registration

Collaborators and Investigators

• Sponsor: Guiping People's Hospital
• Investigators: Principal Investigator: Yaocan Xu, MD, Guiping People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: November 24, 2024
• First Submitted That Met QC Criteria: November 25, 2024
• First Posted (Estimated): November 27, 2024

Study Record Updates

• Last Update Posted (Estimated): November 27, 2024
• Last Update Submitted That Met QC Criteria: November 25, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma; radiotherapy; PD-1 Inhibitors; SFRT
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Immune Checkpoint Inhibitors
• Other Study ID Numbers: GuipingPH-HCC-SFRT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No