Hyperpolarized 13C-MRI in Patients With Hepatocellular Carcinoma Undergoing Radiotherapy, Atezolizumab, and Bevacizumab

Hyperpolarized 13C-MRI, Metabolomics, and Radiomics for Immune Response Prediction in Patients With Hepatocellular Carcinoma Undergoing Radiotherapy, Atezolizumab, and Bevacizumab

Increased pyruvate-to-lactate conversion is a hallmark of HCC metabolism. In parallel, activation of pro-inflammatory immune cells triggers a metabolic switch towards anaerobic glycolysis. Hyperpolarized carbon-13 (13C) pyruvate MRI is a state-of-the-art non-invasive imaging method that offers real-time insights into tissue metabolism. Recent studies have demonstrated its promising potential in predicting responses to radiotherapy and immunotherapy in solid tumors, given the significance of pyruvate as a downstream metabolite in glycolysis. However, its application in assessing treatment response in hepatocellular carcinoma (HCC) patients remains unclear. The establishment of quantitative imaging biomarkers for predicting responses to radio-immunotherapy is an unmet need in the management of HCC patients.

While radiotherapy (RT) effectively controls localized tumors through the induction of unrepairable DNA double-stranded breaks (DSBs) and cell death, its therapeutic efficacy on distal, non-irradiated tumor cells is limited, with out-of-field recurrence being a common pattern of failure in HCC patients treated with high-dose irradiation. Atezolizumab (anti-programmed death-ligand 1; anti-PD-L1) in conjunction with bevacizumab (anti-vascular endothelial growth factor; anti-VEGF) has recently emerged as the standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Despite an objective response rate (ORR) of only 27%, the majority of patients succumb to HCC progression and liver failure. Our preclinical study (Hsieh et al., Science Immunology 2022) uncovered that RT, when combined with PD-L1/PD-1 blockade, induces immunogenic cell death and tumor antigen cross-presentation in antigen-presenting cells, enhancing systemic antitumor T cell responses in murine tumor models. Recent retrospective cohorts suggest that RT targeting all hepatic tumors combined with PD-L1/programmed death-1 (PD-1) blockade is associated with an improved ORR and median progression-free survival (PFS) in patients with unresectable HCC, demonstrating a favorable safety profile. The synergistic antitumor effects of this combination therapy with RT, atezolizumab, and bevacizumab have led to its increasing adoption in routine clinical practice.

This phase II non-randomized trial aims to prospectively investigate the predictive value of hyperpolarized 13C-MRI, along with comprehensive metabolomics and radiomics analyses, for immune response assessment including tumor control outcomes and toxicity in patients with HCC undergoing radiotherapy, atezolizumab, and bevacizumab.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma (HCC)
• Intervention / Treatment: Diagnostic test: Hyperpolarized 13C pyruvate MRI

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

Contacts and Locations

• Study Contact: Name: Rodney Cheng-En Hsieh, MD, PhD; Phone Number: 7000 +886-3-328-1200; Email: chsieh@cgmh.org.tw

Study Locations

• Taiwan
  • Taoyuan City, Taiwan, 333
    • Recruiting
    • Chang Gung Memorial Hospital at Linkou
    • Contact: Rodney Cheng-En Hsieh, MD, PhD; Phone Number: 7000 +886-3-328-1200; Email: rodney445@gmail.com
    • Principal Investigator: Rodney Cheng En Hsieh, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Participants must have diagnosis of HCC that is deemed unsuitable for surgical resection or transplant and will undergo radiotherapy, atezolizumab, and bevacizumab. 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 criteria listed below:

   • Histologically or cytologically proven diagnosis of HCC.
   • Typical arterial enhancement and delayed washout on multiphasic CT or MRI.
2. Age ≥18 years at the time of signing informed consent document.
3. ECOG performance status 0-1.
4. Barcelona Clinic Liver Cancer (BCLC) stages Intermediate (B) or Advanced (C).
5. Child-Pugh score 5-6 liver function within 28 days of study registration.
6. Documented virology status of hepatitis B virus (HBV), as confirmed by screening HBV serology test.
7. Documented virology status of hepatitis C virus (HCV), as confirmed by screening HCV serology test.
8. Ability to understand and the willingness to sign a written informed consent document

9. 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
10. The medical team, experienced in liver cancer treatment, has evaluated and confirmed that the benefits outweigh the risks for participants receiving proton or photon radiation therapy combined with atezolizumab and bevacizumab.

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/hepatic arterial yttrium therapy, at any time
4. Untreated active hepatitis B or hepatitis C
5. Moderate to severe or intractable ascites
6. Presence of distant metastases
7. Untreated or incomplete treated esophageal or gastric varices

8. 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
9. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
10. Prior solid organ transplantation.
11. 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.
12. Prior or active thrombotic or bleeding disorders, hemoptysis, cerebral vascular accident, significant cardiac disease (ischemic or congestive heart failure), or gastrointestinal perforation.
13. Inability to treat all sites of disease by proton radiotherapy (such as extrahepatic metastases or massive liver tumors whereby the liver constraints cannot be met for covering all sites of liver tumors using radiotherapy.)
14. Known HIV infection.
15. Conditions not suitable for magnetic resonance imaging (MRI) include the presence of strongly magnetic arterial clips in the brain, cardiac pacemakers, cochlear implants, and claustrophobia.
16. Concurrent medical conditions that may impact patients during MRI examination include active infections, symptomatic congestive heart failure, uncontrollable angina, arrhythmias, mental disorders, difficulty breathing, or diarrhea.
17. An endoscopy report within the past six months indicates a high risk for upper gastrointestinal bleeding, and the patient has not received complete treatment for its prevention.
18. Individuals who are allergic to hyperpolarized 13C pyruvate, atezolizumab, bevacizumab, or any ingredients contained in these medications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• 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: Hyperpolarized 13C pyruvate MRI; Hyperpolarized 13C pyruvate MRI before and 2-5 weeks after radiotherapy combined with atezolizumab and bevacizumab	Diagnostic test: Hyperpolarized 13C pyruvate MRI; The subject enrolled in this trial will receive DNP-MRI scanning for two times through hyperpolarized [1-13C]pyruvate injection (~250 mM, 0.43 mL/Kg) before and 2-5 weeks after radiotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dynamic Nuclear Polarization (DNP)	Dynamic Nuclear Polarization (DNP) conversion flux (pyruvate-to-lactate conversion rate [Kpl] and area under the curve [AUC]) before radiotherapy combined with atezolizumab and bevacizumab	4 months
Dynamic Nuclear Polarization (DNP)	Dynamic Nuclear Polarization (DNP) conversion flux (pyruvate-to-lactate conversion rate [Kpl] and area under the curve [AUC]) 2-5 weeks after radiotherapy combined with atezolizumab and bevacizumab	4 month

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
Overall survival (OS)	OS is defined as the time from signing the informed consent to death from any cause.	12 months
Progression free survival (PFS) by RECIST1.1	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
Local control (LC) by RECIST1.1	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) by RECIST1.1	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) by RECIST1.1	ORR is defined as a complete or partial response according to RECIST1.1	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in myeloid-derived suppressor cell (MDSC) level in peripheral blood	We will measure the level of Lin- HLA-DR- CD11b+ MDSCs in peripheral blood using flow cytometry before and 2-5 weeks after radiotherapy.	4 months

Collaborators and Investigators

• Sponsor: Chang Gung Memorial Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2025
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): September 30, 2031

Study Registration Dates

• First Submitted: September 18, 2024
• First Submitted That Met QC Criteria: September 18, 2024
• First Posted (Actual): September 20, 2024

Study Record Updates

• Last Update Posted (Actual): May 14, 2025
• Last Update Submitted That Met QC Criteria: May 9, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: HCC; Bevacizumab; Metabolomics; Radiotherapy; Atezolizumab; Hyperpolarized 13C-MRI
• 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
• Other Study ID Numbers: 2401190005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The sharing of individual participant data (IPD) requires IRB approval.

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