ALERT-HCC: Atezolizumab Plus Bevacizumab Alone or Combined With External Beam Radiotherapy for HCC With Macrovascular Invasion

Sponsor

Asan Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT05992220

Collaborator

Seoul National University Hospital (Other), Hanyang University (Other), Soon Chun Hyang University (Other)

138

Enrollment

Location

Arms

40.3

Anticipated Duration (Months)

3.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma Hepatocellular Cancer Hepatocellular Carcinoma Non-resectable Hepatocellular Carcinoma Stage IV Liver Cancer	Radiation: Atezolizumab plus bevacizumab, combined EBRT to vascular invasion Drug: Atezolizumab plus bevacizumab	Phase 2

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

138 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

randomized, multicenter, open-label studyrandomized, multicenter, open-label study

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Oct 22, 2022

Anticipated Primary Completion Date :

Mar 1, 2026

Anticipated Study Completion Date :

Mar 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radiotherapy combination Atezolizumab+Bevacizumab, combined EBRT to vascular invasion 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 A+B, and will be delivered in accordance with institutional protocol.	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 discretion of the investigator. The target dose is 45 Gy, however, the total dose can be reduced as low as 30 Gy according to the liver function, liver volumes, or the maximum dose to the stomach/duodenum during the planning process according to the judgment of the radiation oncologist of each participating sites.
Active Comparator: 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.	Drug: Atezolizumab plus bevacizumab Atezolizumab plus bevacizumab q3w

Arm

Intervention/Treatment

Experimental: Radiotherapy combination

Atezolizumab+Bevacizumab, combined EBRT to vascular invasion 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 A+B, and will be delivered in accordance with institutional protocol.

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 discretion of the investigator. The target dose is 45 Gy, however, the total dose can be reduced as low as 30 Gy according to the liver function, liver volumes, or the maximum dose to the stomach/duodenum during the planning process according to the judgment of the radiation oncologist of each participating sites.

Active Comparator: 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.

Drug: Atezolizumab plus bevacizumab

Atezolizumab plus bevacizumab q3w

Outcome Measures

Primary Outcome Measures

progression-free survival rate [up to approximately 3 years]
Randomization to the first occurrence of disease progression or death from any cause, whichever occurs first

Secondary Outcome Measures

Overall survival rate [up to approximately 3 years]
Randomization to death from any cause, through the end of study
Objective response [up to approximately 3 years]
complete response or partial response as determined by the Investigator according to RECIST V1.1
Adverse reaction rate [through study completion, up to approximately 3 years]
Adverse reaction rate assessed by CTCAE version 5
Time to deterioration [through study completion, up to approximately 3 years]
The time from randomization to first deterioration (decrease from baseline of ≥10 points) in the patient-reported global health status (GHS) / Quality of life (QoL), physical function, or role function scales of the EORTC QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks
Duration of response [up to approximately 3 years]
the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression or death is documented, whichever occurs first. DOR will be assessed in patients who had an objective response.
Tumor marker response (AFP, PIVKA-II) [through study completion, up to approximately 3 years]
The decrease of >20% in serum concentration of each marker from baseline across all time points during study period.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 79 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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