Atezolizumab and Bevacizumab With Proton Radiotherapy for Unresectable Hepatocellular Carcinoma (ProtonAB)

Investigation of Antitumor Immune Response in Patients With Unresectable Hepatocellular Carcinoma Undergoing Proton Radiotherapy Combined With Atezolizumab and Bevacizumab

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.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma Non-resectable
• Intervention / Treatment: Drug: Atezolizumab; Drug: Bevacizumab; Radiation: Proton radiotherapy

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rodney Cheng-En Hsieh, MD, PhD; Phone Number: 7000 88633281200; Email: rodney445@gmail.com

Study Locations

• Taiwan
  • Taoyuan City, Taiwan, 333
    • Recruiting
    • Chang Gung Memorial Hospital at Linkou
    • Contact: Rodney Cheng-En Hsieh, MD, PhD; Phone Number: 7000 +88633281200; Email: rodney445@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

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 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: Atezolizumab and bevacizumab with proton radiotherapy; Patients undergo Atezolizumab and Bevacizumab with proton radiotherapy.

Drug: Atezolizumab; Atezolizumab 1200 mg will be administered as an IV infusion on Day 1 of each cycle, with cycles occurring every 3 weeks. The initial dose will be delivered over 60 (± 15) minutes, and if well-tolerated, subsequent infusions may be given over 30 minutes. For patients who achieve a complete response (CR) within one year of treatment, atezolizumab should be continuously used for a year. For patients who experience a partial response (PR), atezolizumab should be continued until achieving CR or experiencing progressive disease (PD). Patients with stable disease should receive atezolizumab for 6 months. In the case of PD, atezolizumab should be discontinued at the time when PD is confirmed.; Drug: Bevacizumab; Bevacizumab 15 mg/kg will be administered as an IV infusion on Day 1 of each 3-week cycle. The initial dose will be delivered over 90 minutes (±15 minutes), and if well-tolerated, subsequent infusions may be given over 60 minutes. For patients who achieve a complete response (CR) within one year of treatment, bevacizumab should be continuously used for a year. In the case of patients experiencing a partial response (PR), bevacizumab should be continued until achieving CR or experiencing progressive disease (PD). Patients with stable disease should receive bevacizumab for 6 months. In the event of PD, bevacizumab should be discontinued when PD is confirmed. Temporary withholding or dose reduction of bevacizumab is permitted if patients experience adverse events such as bleeding episodes, severe hypertension, or proteinuria at the discretion of the treating physician.; Radiation: Proton radiotherapy; 72.6 CGE in 22 fractions for tumors ≤1 cm from the hepatic hilum, bowel, and heart.; 66 CGE in 10 fractions for tumors >1 cm from the hepatic hilum, bowel, and heart.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	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.	12 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Chang Gung Memorial Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2023
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): September 30, 2030

Study Registration Dates

• First Submitted: November 7, 2023
• First Submitted That Met QC Criteria: November 9, 2023
• First Posted (Actual): November 15, 2023

Study Record Updates

• Last Update Posted (Estimated): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: HCC; Bevacizumab; VEGF; Atezolizumab; PD-L1; Proton radiotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Immune Checkpoint Inhibitors; Bevacizumab; Atezolizumab
• Other Study ID Numbers: 202301234A3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Sharing individual participant data (IPD) with other researchers requires IRB review and approval. Presently, we do not have a plan to provide IPD to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No