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

NCT06605664 | Recruiting Phase 2

• 1 other identifier: 2401190005
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hepatocellular Carcinoma (HCC)

Keywords

Hyperpolarized 13C-MRI; HCC; Radiotherapy; Metabolomics; Atezolizumab; Bevacizumab

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Progression free survival (PFS) by RECIST1.1

  12 months

• Local control (LC) by RECIST1.1

  12 months

• Time to progression (TTP) by RECIST1.1

  12 months

• Overall Response Rate (ORR) by RECIST1.1

  12 months

• Overall survival (OS)

  12 months

Other Outcomes (1)

• Change in myeloid-derived suppressor cell (MDSC) level in peripheral blood

  4 months

Study Arms (1)

Hyperpolarized 13C pyruvate MRI

EXPERIMENTAL

Hyperpolarized 13C pyruvate MRI before and 2-5 weeks after radiotherapy combined with atezolizumab and bevacizumab

Diagnostic Test: Hyperpolarized 13C pyruvate MRI

Interventions

Hyperpolarized 13C pyruvate MRI DIAGNOSTIC_TEST

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.

Hyperpolarized 13C pyruvate MRI

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Chang Gung Memorial Hospital: lead

Study Sites (1)

Chang Gung Memorial Hospital at Linkou

Taoyuan, 333, Taiwan

RECRUITING

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Central Study Contacts

Rodney Cheng-En Hsieh, MD, PhD

CONTACT

+886-3-328-1200; chsieh@cgmh.org.tw

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Attending Physician

Model Details: Single arm of hyperpolarized 13C pyruvate MRI

Study Record Dates

• First Submitted: September 18, 2024
• First Posted: September 20, 2024
• Study Start: May 1, 2025
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): September 30, 2031
• Last Updated: May 14, 2025

Record last verified: 2025-05

Locations

TW (1)