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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma; Liver Cancer; Hepatocellular Carcinoma Non-resectable; Hepatocellular Cancer; Hepatocellular Carcinoma Stage IV
• Intervention / Treatment: Radiation: Atezolizumab plus bevacizumab, combined EBRT to vascular invasion; Drug: Atezolizumab plus bevacizumab

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 Type: Interventional
• Enrollment (Estimated): 138
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jihyun An; Phone Number: 82-31-560-2209; Email: starlit1@naver.com
• Study Contact Backup: Name: Ju Hyun Shim; Email: s5854@amc.seoul.kr

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Recruiting
    • Asan Medical Center
    • Contact: Ju Hyun Shim

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression-free survival rate	Randomization to the first occurrence of disease progression or death from any cause, whichever occurs first	up to approximately 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival rate	Randomization to death from any cause, through the end of study	up to approximately 3 years
Objective response	complete response or partial response as determined by the Investigator according to RECIST V1.1	up to approximately 3 years
Adverse reaction rate	Adverse reaction rate assessed by CTCAE version 5	through study completion, up to approximately 3 years
Time to deterioration	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	through study completion, up to approximately 3 years
Duration of response	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.	up to approximately 3 years
Tumor marker response (AFP, PIVKA-II)	The decrease of >20% in serum concentration of each marker from baseline across all time points during study period.	through study completion, up to approximately 3 years

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Collaborators: Seoul National University Hospital; Hanyang University; Soon Chun Hyang University
• Investigators: Principal Investigator: Ju Hyun Shim, Asan Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2022
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: July 27, 2023
• First Submitted That Met QC Criteria: August 7, 2023
• First Posted (Actual): August 15, 2023

Study Record Updates

• Last Update Posted (Actual): August 15, 2023
• Last Update Submitted That Met QC Criteria: August 7, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: HCC; vascular invasion; portal vein tumor thrombosis; BCLC stage C
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Immune Checkpoint Inhibitors; Bevacizumab; Antibodies, Monoclonal; Atezolizumab
• Other Study ID Numbers: KCT0007365 (Registry Identifier: CRIS (International Clinical Trials Registry Platform))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No