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Atezolizumab and Bevacizumab With Proton Radiotherapy for Unresectable Hepatocellular Carcinoma

ConditionHepatocellular Carcinoma Non-resectable
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorChang Gung Memorial Hospital

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

Disqualifiers

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

Trial design

Design model

Single group

Treatments tested in this trial

  • Atezolizumab

    Drug

    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

    Drug

    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.

  • Proton radiotherapy

    Radiation

    * 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.

Treatment groups

45 Participants
are divided into 1 treatment group
Group A: Atezolizumab and bevacizumab with proton radiotherapyExperimental treatment 3 interventions

Trial outcomes

Primary outcomes

1

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.

Time frame
12 months

Secondary outcomes

1

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.

Time frame
12 months
2

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.

Time frame
12 months
3

Overall Response Rate (ORR)

ORR is defined as a complete or partial response according to RECIST1.1.

Time frame
12 months
4

Overall survival (OS)

OS is defined as the time from signing the informed consent to death from any cause.

Time frame
12 months

Other outcomes

Sponsors and contacts

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Chang Gung Memorial Hospital

Lead sponsor

Source ClinicalTrials.gov
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