A single-arm phase II study of atezolizumab plus bevacizumab after SBRT in patients with unresectable hepatocellular carcinoma with macrovascular invasion

JRCT ID: jRCTs031210694

Registered date:23/03/2022

Basic Information

• Recruitment status: Suspended
• Health condition(s) or Problem(s) studied: hepatocellular carcinoma
• Date of first enrollment: 29/11/2022
• Target sample size: 36
• Study type: Interventional
• Intervention(s): Atezolizumab plus bevacizumab combination therapy after stereotactic body irradiation for portal vein tumour invasion (Vp3/4) or hepatic vein tumour invasion (Vv2/3)

Outcome(s)

• Primary Outcome: The study consists of a safety part and a phase II part, each with its own primary endpoint. In the Safety Part, the primary endpoint is " the incidence of treatment-related dose-limiting toxicity in CTCAE v.5.0-JCOG within 60 days from the last day of SBRT (day 0). In the Phase II part of the study, the primary endpoint is " 1-year survival rate", and safety and efficacy are evaluated in patients enrolled in the study's safety and Phase II parts.

Secondary Outcome

1) The incidence of treatment-related adverse events of Grade 3 or higher in CTCAE v.5.0-JCOG
2) Response rate and disease control rate in RECIST v1.1
3) Progression-free survival
4) Response rate and disease control rate in modified RECIST
5) Overall survival

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

A. Signed informed consent Form is obtained
B. confirmed diagnosis of hepatocellular carcinoma by histopathological or imaging findings
C. Unresectable hepatocellular carcinoma not eligible for local puncture therapy (percutaneous ethanol injection, percutaneous radiofrequency ablation, microwave coagulation necrosis) or radiotherapy alone.
D. The diagnosis of primary hepatocellular carcinoma with either Vp3/4 or Vv2/3 according to the 6th edition of the Hepatocellular Carcinoma Treatment Guidelines.
E. The following criteria of prior systemic therapy for hepatocellular carcinoma are met.
(i) Safety part: "No prior systemic therapy for HCC" or "Second-line systemic therapy after sorafenib or lenvatinib without Vp3/4 or Vv2/3 on imaging findings at the start of the first-line systemic therapy".
(ii) Phase II part: No prior systemic drug therapy for hepatocellular carcinoma
F. At least one measurable (per RECIST v1.1) lesion within 28 days prior to enrollment
G. Tumor evaluation by contrast-enhanced CT or MRI is available
H. ECOG Performance Status of 0 or 1
I. Child-Pugh classification A liver function
J. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 7 days prior to enrollment treatment unless otherwise specified:
K. Screening test for HBV, HBV-DNA level less than 500IU/mL obtained at the time of enrollment for patients with continuous HBV infection, and anti-HBV treatment based on the latest guidelines of the Japanese Society of Hepatology for at least 14 days prior to study treatment, and during the study treatment period

Exclude criteria

A. Tumour invasion / tumour thrombosis in the splenic vein, superior mesenteric vein, or right atrium on imaging studies within 28 days prior to enrolment
B. History of hepatic encephalopathy within 180 days prior to enrollment
C. History of cerebral meningitis and tumour invasion of the central nervous system
D. Active or history of autoimmune disease requiring systemic treatment (steroids or immunosuppressive drugs)
E. A history of active primary immunodeficiency
F. Active or history of idiopathic pulmonary fibrosis, drug-induced pneumonia, radiation pneumonitis, idiopathic pneumonia or severe emphysema
G. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident), unstable arrhythmia, or unstable
angina within 180 days prior to enrollment
H.Thrombosis or embolism within 180 days prior to enrolment.
I. Clinically uncontrolled hypertension
J. Clinically uncontrolled pericardial effusion
K. Clinically uncontrolled diabetes mellitus
L. History of malignant tumour within 2 years prior to enrolment (except basal cell carcinoma/squamous cell carcinoma of the skin after radical treatment, prostate cancer after radical treatment, cancer of the gastrointestinal tract after radical endoscopic resection, intraepithelial carcinoma, etc.)
M. With active infectious diseases with systemic treatment, except hepatitis virus infection
N. Known active tuberculosis.
O. Histroy of Significant surgical procedure (e.g. open chest, laparotomy, thoracotomy, laparoscopy) undergone an open abdominal biopsy or suturing for significant trauma, or scheduled for major surgical procedure (open chest or laparotomy) during the study period
P. Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2 agents or agents targeting other co-stimulatory or co-inhibitory T-cell receptors (e.g. CTLA-4, OX-40, CD137)
Q. History of allergy to chimeric or humanized antibodies or fusion proteins
R. Active untreated or under treatment gastroesophageal varices on upper endoscopy within 28 days prior to enrollment
S. Clinically uncontrolled pleural effusion or ascites of moderate volume or greater
T. TumoursTumours in the mediastinum within 30 mm of the aorta or tracheal bifurcation 6 months prior to enrolment
U. Previous radiotherapy in the planned target volume for radiotherapy in this study
V. Receiving antithrombotic therapy at therapeutic doses.
However, prophylactic antithrombotic therapy is acceptable as long as it is in accordance with the respective national guidelines and drug label. Details of '4 Prophylactic antithrombotic therapy' are provided in section 6.5.3.1 'Prescribed concomitant medications and therapies
W. Women who cannot consent to contraception for 9 months after the last dose of bevacizumab and 11 months after the last dose of atezolizumab, who are pregnant, of childbearing potential, within 28 days postpartum, or breastfeeding. Men who wish their partner to become pregnant within 6 months of the last dose of bevacizumab and within 8 months of the last dose of atezolizumab
X. History of or complications from any disease, treatment or laboratory abnormality that would preclude the patient from participating in the study in the opinion of the treating physician

Related Information

• Primary Sponsor: Maeda Shin
• Source(s) of Monetary Support: Chugai Pharmaceutical Co., Ltd.