Atezolizumab Plus Bevacizumab Alone or Combined with External Beam Radiotherapy for HCC with Macrovascular Invasion

Official title

A Randomized, Multicenter, Open-Label, Phase II Trial of Atezolizumab Plus Bevacizumab Alone or Combined with External Beam RadioTherapy for HepatoCellular Carcinoma with Macrovascular Invasion (ALERT-HCC)

Overview

The recent global IMbrave150 study evaluated the combination of atezolizumab and bevacizumab versus sorafenib in 501 patients with advanced or metastatic Hepatocellular Carcinoma (HCC). The median overall survival (OS) was notably better in the atezolizumab/bevacizumab group. However, for HCC patients with intrahepatic macrovascular invasion (MVI), the prognosis remains poor, indicating a significant unmet need in this group. External Beam Radiotherapy (EBRT) has shown promising results in treating HCC with MVI, especially when used in combination with trans-arterial chemoembolization (TACE). It has been reported that radiotherapy may make tumor cells more susceptible to immune-mediated therapy, potentially enhancing the effects of atezolizumab and bevacizumab. Thus, this study aims to investigate the efficacy and safety of atezolizumab/bevacizumab alone versus atezolizumab/bevacizumab in combination with EBRT in HCC patients with macrovascular invasion.

Detailed description

A total of 138 subjects are randomly assigned to one of two treatment groups (69 patients in the atezolizumab+bevacizumab group and 69 patients in the Atezolizumab plus Bevacizumab combined EBRT group).

* Radiotherapy combination:

* Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle. * Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle. * The external beam radiotherapy will commence after day 2 of the first cycle of Atezolizumab+Bevacizumab, and will be delivered in accordance with institutional protocol. * Atezolizumab+Bevacizumab:

* Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21day cycle. * Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21day cycle.

Additional study identifiers: This study was also registered on the WHO's International Clinical Trials Registry Platform, CRIS, before the first participant was enrolled (ID: KCT0007365, Date of registration: 2022-06-08).

Interventions

• Radiation Atezolizumab plus bevacizumab, combined EBRT to vascular invasion
  The external beam radiotherapy will commence after day 2 of the first cycle of atezolizumab+bevacizumab, and will be delivered in accordance with institutional protocol. 3D-conformal radiotherapy technique is used to determine target volumes, radiation ports, and dose prescriptions by using a 3D radiotherapy planning system. The gross tumor volume (GTV) includes vascular invasion and a 2-cm margin into the contiguous HCC. The GTV can consist of the entire HCC and vascular invasion at the discr
• Drug Atezolizumab plus bevacizumab
  Atezolizumab plus bevacizumab q3w

Primary outcome measures

• progression-free survival rate [Time frame: up to approximately 3 years]

Secondary outcome measures (6)

• Overall survival rate [Time frame: up to approximately 3 years]
• Objective response [Time frame: up to approximately 3 years]
• Adverse reaction rate [Time frame: through study completion, up to approximately 3 years]
• Time to deterioration [Time frame: through study completion, up to approximately 3 years]
• Duration of response [Time frame: up to approximately 3 years]
• Tumor marker response (AFP, PIVKA-II) [Time frame: through study completion, up to approximately 3 years]

Eligibility criteria

Inclusion criteria

• Older than 19 years of age, lower than 80 years of age
• Child-Pugh class A hepatic function
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1
• Patients with HCC \[diagnosed according to AASLD guidelines\] invading the intrahepatic vascular system
• No prior systemic therapy for HCC
• At least one measurable HCC lesion with ≥ 1cm diameter
• Adequate hematologic and organ function

• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1,000 /mm3
• Platelet ≥ 50,000/ mm3 without transfusion
• Total bilirubin ≤ 2.5 mg/dL

Exclusion criteria

• Treatment history of prior systemic treatment of HCC
• Liver transplant recipients
• Patients with peptic ulcer, untreated or incompletely treated varices with bleeding or high-risk for bleeding
• Any serious illness (e.g., active infection or inflammatory condition) or uncontrolled severe medical comorbidity
• A history of treated malignancy (other than HCC) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding two years
• Abdominal/pelvic radiotherapy within 28 days prior to initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days prior to initiation of study treatment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

South Korea · 1 center

• Asan Medical Center — Seoul

Identifiers

NCT: NCT05992220 · KCT0007365 · KCT0007365

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗