Atezolizumab and Bevacizumab With Proton Radiotherapy for Unresectable Hepatocellular Carcinoma

Hepatocellular Carcinoma Non-resectable Clinical Trial

— ProtonAB  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06133062
• Other study ID #: 202301234A3
• Status: Recruiting
• Phase: Phase 2
• Start date: November 16, 2023
• Est. completion date: September 30, 2030

Study information

• Verified date: November 2023
• Source: Chang Gung Memorial Hospital
• Contact: Rodney Cheng-En Hsieh, MD, PhD
• Phone: 88633281200
• Email: rodney445[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 45
• Est. completion date: September 30, 2030
• Est. primary completion date: September 30, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma Non-resectable

Intervention

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.
• 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.

Locations

Country	Name	City	State
Taiwan	Chang Gung Memorial Hospital at Linkou	Taoyuan City

Sponsors (1)

Lead Sponsor	Collaborator
Chang Gung Memorial Hospital

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Overall Response Rate (ORR)	ORR is defined as a complete or partial response according to RECIST1.1.	12 months
Secondary	Overall survival (OS)	OS is defined as the time from signing the informed consent to death from any cause.	12 months
Secondary	Incidence and severity of adverse events	Adverse events will be graded using CTCAE v5	12 months