RACB Study

JRCT ID: jRCTs051210148

Registered date:07/01/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Hepatocellular Carcinoma
• Date of first enrollment: 04/03/2022
• Target sample size: 50
• Study type: Interventional
• Intervention(s): To investigate the efficacy of combined atezolizumab and bevacizumab therapy and multimodality treatment using surgical resection for unresectable hepatocellular carcinoma.

Outcome(s)

• Primary Outcome: Progression-free survival

Secondary Outcome

1) Overall response rate (ORR)
2) Progression-free survival (PFS)
3) Overall survival(OS)
4) Surgical resection rate
5) Macroscopic curative resection rate
6) Surgical resection rate with effective protocol treatments
7) ICGR15 after chemotherapy

Key inclusion & exclusion criteria

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

Include criteria

1. Diagnosed with hepatocellular carcinoma and no prior medical therapy (sorafenib, lenvatinib and immunotherapy) for hepatocellular carcinoma
2.Have at least one target lesion based on RECISTver1.1 criteria
3.Age 20 years or older
4.Eastern Cooperative Oncology Group Performance Status (PS) 0-1
5.Adequate organ function
If more than one test result is present within the study period, the most recent one to enrollment should be employed, and no blood transfusion and administration of hematopoietic factor products have been performed within 30 days before the test day for measurement prior to enrollment.
WBC >=3000/mm3, neutrophil count >=1500/mm3, Hb >=8.5g/dL, platelet count >=60,000/mm3, total bilirubin <=3.0 mg/dL, serum albumin >=2.8g/dL, AST (GOT), ALT (GPT) <=5 times the upper limit of each medical institution (excluding cases associated with cancer)
Serum creatinine <=1.5 times the upper limit of each medical institution
Urine protein<= 2+
Urine protein/creatinine ratio <2.0 at any time when urine protein is >=3+ (urine protein < 2.0g in case of 24-hour urine collection).
6.Child Pugh score of 5-6 within 14 days prior to enrollment
7.No other active malignancies
8.A patient's written informed consent (IC) has been obtained after sufficient explanation of study given to the patient.
9. Hepatocellular carcinoma tumor conditions are classified as A, B, C, D, or E. *1 Unresectable hepatocellular carcinoma.
A) [Intrahepatic vascular invasion] Intrahepatic tumors are classified as Vv2-3, Vp2-4, and B2-4.
No extrahepatic tumor.
Vv2: Invasion/tumor thrombus is observed in either the right middle and left hepatic vein main trunks, the inferior right hepatic vein, or the short hepatic vein.
Vv3: Invasion and tumour thrombus in the inferior vena cava.

Vp2: Invasion and tumour thrombus in the secondary branch of the portal vein.
Vp3: Invasion and tumour thrombus in the primary branch of the portal vein.
Vp4: Invasion and tumour thrombus are observed in the main trunk of the portal vein and the contralateral portal vein branches.

B2: Invasion and tumor thrombus in the secondary branch of the bile duct.
B3: Invasion and tumor thrombus in the primary branch of the bile duct.
B4: Invasion and tumor thrombus in the common bile duct.
B) [Synchronous extrahepatic metastases] Intrahepatic tumors are resectable without gross vascular invasion. Extrahepatic tumors such as distant organ metastases, peritoneal metastases, lymph node metastases, and tumor dissemination along the puncture route are present. *2
C) [Intrahepatic vascular invasion and synchronous extrahepatic metastasis]. Intrahepatic tumor is Vv2-3, Vp2-4, and B2-4, and diagnosed as synchronous extrahepatic metastasis*2
D) [ Macroscopic residual tumor] Applied when complete resection of intrahepatic tumor was difficult but therapeutically meaningful surgical resection was performed.*3
E) [Metachronous extrahepatic metastases] No or controllable intrahepatic tumor. Diagnosed with extrahepatic metastasis *4.
*1 The oncological condition of A-E is poor in prognosis and oncologically unresectable. It is also classified as unresectable according to the BCLC staging system frequently used worldwide (Appendix 3). In the past, surgical resection for hepatocellular carcinoma with extrahepatic metastasis and vascular invasion has been performed only in some centers with a large number of resected cases of hepatocellular carcinoma, but the long-term prognosis is poorer compared with cases without hepatocellular carcinoma.
*2 Limited to a single organ metastasis. Adrenal gland: No bilateral metastasis. Regarding lymph node metastasis, it is limited to patients with intra-abdominal metastasis. The upper limit of the number of tumors is 5 lung metastases, 2 lymph node metastases, 5 peritoneal metastases, 1 bone metastasis, and 1 paracentesis route recurrence. When it is difficult to diagnose extrahepatic metastasis, eligibility of patients for the study should be evaluated comprehensively at each medical institution following appropriate examinations such as PET.
*3 Survival benefit or improvement in QOL is expected.
*4 Patients with bone metastases are excluded but otherwise comply with *2.

Exclude criteria

1. Currently receiving full doses of oral or parenteral anticoagulants or thrombolytics intended for treatment (not for prophylaxis) or has received them within 10 days prior to enrollment*.
*Examples: Current use of aspirin (>325 mg/day), dipyridamole, ticlopidine, clopidogrel, or cilostazol, or used within 10 days before enrollment.
2. Have untreated or not adequately treated esophageal varices and/or varices with or at high risk of bleeding, or a history of bleeding due to esophageal varices and/or varices within 180 days prior to enrollment. (All varices of any size should be examined by esophagogastroduodenoscopy (EGD) and treated prophylactically according to the standard therapy of the participating medical institutions before enrollment. If the presence of varices is ruled out by EGD within 180 days before enrollment, repeat procedures will not be required.)
3. Had thrombosis and/or embolism within 180 days before enrollment.
4. Has undergone major surgical procedures (thoracotomy, open surgery, thoracoscopic surgery, laparoscopic surgery, etc.) within 28 days before enrollment. Patients have undergone open wound biopsy, or suture procedures for major trauma, or will receive major surgical procedures (thoracotomy, open surgery) during the study period.
5. Has received systemic immunostimulatory agents (e.g., interferon, interleukin-2 [IL-2]) within 180 days prior to enrollment.
6. Has received systemic immunosuppressants (e.g., corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, tumor necrosis factor [TNF]-alpha inhibitors) within 14 days before enrollment or expected to receive systemic immunosuppressants during the study period. Except for patients treated with mineralocorticoids (such as fludrocortisone) or corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma.
7.History and complications of autoimmune disease within 180 days prior to enrollment
8. History of active double cancer or malignancy * (synchronous double cancer and metachronous double cancer with disease-free interval < 3 years). * Excluding early-stage cancers with low risk of recurrence that were treated appropriately with radical treatment, such as cervical carcinoma in situ, basal cell carcinoma, superficial bladder tumor, early esophageal cancer, early gastric cancer, and early colorectal cancer.
9. Currently participating in another study of unapproved drugs or a study requiring intervention (including a follow-up period).
10.Critical cardiovascular disease (New York Heart Association [NYHA] Class II or higher heart disease, myocardial infarction), unstable arrhythmia or unstable angina in the 90 days prior to enrollment.
11.Pregnant, breastfeeding, positive in pregnancy test (pregnancy tests performed in menstruating women within the past year), women and men unwilling to contraceptive during the study period.
12. Has clinically uncontrolled pleural effusion, pericardial effusion or ascites.
13.Has complications of hepatic encephalopathy
14.Has serious complications as listed below
Uncontrolled hypertension with or without antihypertensive medication
Severe infections (e.g., hospitalization for complications of infection, bacteremia, severe pneumonia) occurred within 28 days before enrollment. Excluding hepatitis B virus (HBV) and hepatitis C virus (HCV).
Currently receiving hemodialysis due to renal failure or has a serious mental illness or allergic reaction to contrast medium interfering with angiography, e*. *Inability to undergo both contrast-enhanced CT and contrast-enhanced MRI (registration is allowed if either CT or MRI is performed)
15. Has a history of serious allergic or anaphylactic reactions to chimeric antibody, humanized antibody, or fusion protein.
16.Hypersensitivity to either Chinese hamster ovary cell-derived products or components of atezolizumab or bevacizumab products.
17.Has a history of hemorrhagic disease, gastrointestinal hemorrhage or active hemoptysis.
18. Difficult to ingest medication
19.HIV-positive
20. Active pulmonary fibrosis or interstitial pneumonia
21.Has received blood transfusions or G-CSF products within 14 days prior to enrollment
22. Poor general condition and the attending physician judges that the patient is not suitable for participating in the study.
*Patients with a history of COVID-19 infection will also be eligible for the study if they meet the above eligibility criteria and none of the exclusion criteria apply.

Related Information

• Primary Sponsor: Hatano Etsuro
• Source(s) of Monetary Support: Chugai Pharmaceutical Co. Ltd.