Atezolizumab and Bevacizumab with Proton Radiotherapy for Unresectable Hepatocellular Carcinoma

Phase 2

Recruiting

• Conditions: Hepatocellular Carcinoma Non-resectable
• Interventions: Drug: Atezolizumab; Drug: Bevacizumab; Radiation: Proton radiotherapy

• Registration Number: NCT06133062
• Lead Sponsor: Chang Gung Memorial Hospital

Brief Summary

Atezolizumab (anti-programmed death-ligand 1; anti-PD-L1) in conjunction with bevacizumab (anti-vascular endothelial growth factor; anti-VEGF) has become the established standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Despite an improved objective response rate (ORR) of 27%, the majority of patients face HCC progression and liver failure \[Finn et al., N Engl J Med 2020\]. Developing a new combined treatment strategy to overcome resistance to anti-PD-L1 and anti-VEGF is essential to improve patient outcomes.

Radiation treatment (RT) is notably effective in managing localized solid tumors and is a fundamental component of unresectable HCC treatment. Recent retrospective cohorts have demonstrated that proton RT targeting all hepatic tumors, along with PD-L1/programmed death-1 (PD-1) blockade, enhances ORR and progression-free survival for unresectable HCC patients, displaying a favorable safety profile (Su et al., Am J Cancer Res. 2022). Our preclinical study (Hsieh et al., Sci Immunol 2022) showcased that RT combined with PD-L1/PD-1 blockade stimulates immunogenic cell death and antigen cross-presentation in murine tumor models, promoting systemic antitumor T cell responses. Nonetheless, it is crucial to verify whether the combined therapy of proton RT, atezolizumab, and bevacizumab triggers synergistic antitumor effects and systemic immune activation in clinical trials for unresectable HCC. This phase II non-randomized trial aims to prospectively evaluate therapeutic efficacy, safety, and immunological responses in patients with unresectable HCC treated with atezolizumab/bevacizumab combined with proton radiotherapy.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-11-07
• Study First Submitted QC: 2023-11-09
• Study First Posted: 2023-11-15
• Study Start: 2023-11-16
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-16
• Last Update Posted: 2025-02-19
• Primary Completion: 2028-09-30
• Study Completion: 2030-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 45

Inclusion Criteria

• Participants must have diagnosis of HCC that is deemed unsuitable for surgical resection or transplant. Participants may have multiple lesions with a total maximal tumor dimension of < 20 cm, and no one lesion > 15 cm. Diagnosis should be confirmed by at least 1 criterion listed below:

  • Histologically or cytologically proven diagnosis of HCC.
  • Typical arterial enhancement and delayed washout on multiphasic CT or MRI.

• Age ≥18 years at the time of signing informed consent document.

• ECOG performance status 0-1.

• Barcelona Clinic Liver Cancer (BCLC) stages Intermediate (B) or Advanced (C).

• Child-Pugh score 5-6 liver function within 28 days of study registration.

• Documented virology status of hepatitis B virus (HBV), as confirmed by screening HBV serology test.

• Documented virology status of hepatitis C virus (HCV), as confirmed by screening HCV serology test.

• Ability to understand and the willingness to sign a written informed consent document

• Adequate bone marrow, liver, and renal function within 4 weeks before study registration

  • Hemoglobin ≥ 9.0 g/dL
  • Absolute neutrophil count (ANC) ≥ 1,000/mm3
  • Platelet count ≥ 50,000/μL
  • Total bilirubin < 2.5 mg/dL
  • Serum albumin >2.8 g/dL
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN)
  • Prothrombin time ≤ 6 seconds prolonged
  • Serum creatinine ≤ 1.5 mg/dL

Exclusion Criteria

• Prior invasive malignancy unless disease free for a minimum of 2 years

• Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields

• Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time

• Untreated active hepatitis B or hepatitis C

• Moderate to severe or intractable ascites

• Presence of distant metastases that cannot be encompassed by proton radiotherapy

• Untreated or incomplete treated esophageal or gastric varices

• 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

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception

• Prior solid organ transplantation.

• Prior or active autoimmune disease (AID) including autoimmune hepatitis, inflammatory bowel disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, and multiple sclerosis.

• Prior or active thrombotic or bleeding disorders, hemoptysis, cerebral vascular accident, significant cardiac disease (ischemic or congestive heart failure), or gastrointestinal perforation.

• Inability to treat all sites of disease by proton radiotherapy (such as extrahepatic metastases or massive liver tumors whereby the liver constraints [ULV/SLV >40%] cannot be met for covering all sites of liver tumors using proton radiotherapy.)

• Known HIV infection.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Atezolizumab and bevacizumab with proton radiotherapy	Proton radiotherapy	Patients undergo Atezolizumab and Bevacizumab with proton radiotherapy.
Atezolizumab and bevacizumab with proton radiotherapy	Bevacizumab	Patients undergo Atezolizumab and Bevacizumab with proton radiotherapy.
Atezolizumab and bevacizumab with proton radiotherapy	Atezolizumab	Patients undergo Atezolizumab and Bevacizumab with proton radiotherapy.

Primary Outcome Measures

Name	Time	Method
Progression free survival (PFS)	12 months	PFS is defined as the time from signing the informed consent to the first occurrence of disease progression or death from any cause (whichever occurs first) according to RECIST1.1.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	12 months	ORR is defined as a complete or partial response according to RECIST1.1.
Local control (LC)	12 months	LC is defined as the time from signing the informed consent to the first occurrence of disease progression in the irradiated field according to RECIST1.1.
Time to progression (TTP)	12 months	TTP is defined as the time from signing the informed consent to the first occurrence of disease progression according to RECIST1.1.
Overall survival (OS)	12 months	OS is defined as the time from signing the informed consent to death from any cause.
Incidence and severity of adverse events	12 months	Adverse events will be graded using CTCAE v5

Trial Locations

Locations (1)

Chang Gung Memorial Hospital at Linkou; 🇨🇳 Taoyuan City, Taiwan