Randomized, multicenter, phase 3 study evaluating the efficacy of IMmunotherapy(Atezolizumab) Plus Anti-VEGF therapy(Bevacizumab) in Combination with Transarterial chemoembolization for unresectable HCC

JRCT ID: jRCTs051230037

Registered date:13/06/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Hepatocellular Carcinoma
• Date of first enrollment: 01/08/2023
• Target sample size: 600
• Study type: Interventional

Intervention(s)

(Atezo+Bev Therapy)
Atezolizumab 1200 mg/body + bevacizumab 15 mg/kg every 3 weeks for patients with unresectable hepatocellular carcinoma.
(TACE + Atezo+Bev Combination therapy)
Patients with unresectable hepatocellular carcinoma who are stable (SD) on imaging evaluation based on Response evaluation criteria in solid tumours version 1.1 (RECIST ver. 1.1) after atezolizumab plus bevacizumab (Atezo+Bev) therapy Atezo+Bev plus transarterial chemoembolization (TACE) for patients with stable (SD) response evaluation criteria in solid tumors version 1.1 (RECIST ver. 1.1) after Atezo+Bev therapy.
(Radical Therapy)
For patients with unresectable hepatocellular carcinoma who have complete response (CR) or partial response (PR) on imaging evaluation based on RECIST ver. 1.1 after Atezo+Bev therapy, radical therapy (surgical resection, radiofrequency ablation [RFA]/microwave ablation [MWA], radical TACE, X-ray/ particle therapy, etc.) to be added to the list.

Outcome(s)

Primary Outcome

(1)Randomized cohort
OS
(2)ABC-conversion cohort
Conversion rate

Secondary Outcome

(1) Randomized cohort
Progression-free survival (PFS)
Objective response rate (ORR)
Duration of response (DOR)
Time to CR (CR)
Conversion rate
Safety
(2) ABC-conversion cohort
OS
PFS
ORR
DOR
Time to CR
Safety

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1)Typical hepatocellular carcinoma confirmed by tissue and histological diagnosis or imaging diagnosis such as dynamic CT (MRI) and AASLD (the American Association for the Study of Liver Diseases) guidelines.
2)Unresectable hepatocellular carcinoma.
3)Barcelona-Clinic Liver Cancer (BCLC)-C (with or without EHS, Vp1-2 if there is vascular invasion) or BCLC A of a single tumour with a maximum size >= 5 cm considered by the responsible physician to be unsuitable for TACE.
4)>= 18 years of age at enrollment.
5)Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
6)At least one intrahepatic target lesion according to RECIST ver.1.1.
7)At least one or more intrahepatic lesions with tumor staining and in which TACE can be performed.
8)No history of systemic therapy for hepatocellular carcinoma.
9)Child-Pugh class A within 14 days prior to enrollment.
10)Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days before enrollment.
If multiple test results are available during the concerned period, the results closest to enrollment will be used. Blood transfusion or hematopoietic factor administration within 30 days before the date of measurements is not permitted.
i.Neutrophil count: >= 1,000/mm^3
ii.Platelet count: >= 50,000/mm^3
iii.Aspartate aminotransferase (AST): <= 150U/L
iv.Alanine aminotransferase (ALT): (males) <= 210U/L, (females) <= 115U/L
v.Total bilirubin: <= 3.0 mg/dL
vi.Serum albumin: >= 2.8 g/dL
vii.Serum creatinine: (males) <= 1.605mg/dL, (females) <= 1.185mg/dL
viii.Urine protein: <= 2+
If >= 3+, urine protein / creatinine ratio: < 2.0 in spot urine (in case of 24-hour urine collection, urine protein < 2.0 g / 24 hr)
11)Personal written informed consent after the study has been fully explained.

Exclude criteria

1) Patient is eligible for radical therapy (surgical resection, RFA) or radical TACE.
2) Vp3 or Vp4.
3) Total of hepatocellular carcinoma occupies more than 50% of the liver volume.
4) Patients who are difficult or at high risk for TACE and who meet the following criteria.
- Severe stenosis or obstruction of the hepatic artery detected by enhanced CT, MRI, or angiography.
- Severe arterial-portal or arterial-venous shunting.
- Moderate to severe intrahepatic bile duct dilatation.
- Previous duodenal papillotomy or biliopancreatic jejunostomy.
- Biliary stenting.
5) Current or recent (within 10 days before enrollment) use of full-dose oral or parenteral Antithrombotics or thrombolytic agents for therapeutic purposes (exclude prophylactic purpose).
6) Thrombosis or embolism within 180 days before enrollment.
7) Untreated or inadequately treated esophageal and/or gastric varices with, or at a high risk of, bleeding, or history of bleeding due to esophageal and/or gastric varices within 180 days pre-enrollment. EGD should be performed pre-enrollment to examine and preemptively treat varices of all sizes following local care standards. No need for re-examination if EGD performed within 180 days pre-enrollment confirmed the absence of varices.
8) Major surgical procedure within 28 days before enrollment (open chest, laparoscopy, thoracoscopic surgery, laparoscopic surgery and etc.); open biopsy or suturing for major trauma; or planned major surgical procedure during the study (open chest, laparoscopy).
9) Treatment with systemic immunostimulatory agents (interferon, interleukin-2 and etc.) within 180 days before enrollment.
10) Treatment with systemic immunosuppressive agents (corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, tumor necrosis factor [TNF]-alpha agents and etc.) within 14 days before enrollment, or anticipated need for systemic immunosuppressive agents during the study treatment, with the following exceptions: treatment with mineralocorticoids (fludrocortisone and etc.) or corticosteroids for chronic obstructive pulmonary disease (COPD), asthma or etc.
11) History within 180 days before enrollment or complication of autoimmune inflammatory disease.
However, the following shall be exceptions.
- The patient has autoimmune-related hypothyroidism and is using thyroid replacement hormone.
- Patients with type 1 diabetes controlled by insulin therapy.
- Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo vulgaris whose symptoms are limited to the skin only, if all of the following conditions are met (e.g., patients with psoriatic arthritis are eligible)
i) The rash covers less than 10% of the body surface area.
ii) Disease is well controlled at baseline and the only treatment required is a low potency topical corticosteroid.
iii) No acute exacerbation of the underlying disease within the past 12 months that requires solarene + UV-A irradiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or potent or oral steroids.
12) History of active overlapping cancer or malignancy* (simultaneous overlapping cancer and metachronous overlapping cancer with a disease-free interval of 2 years or less).
* Following cancer is not defined as active overlapping cancer.
Prostate cancer in clinical stage I, laryngeal cancer with complete response to radiotherapy in clinical stage 0 or I, and completely resected cancers with a 5-year relative survival rate equal to or greater than 95%, such as the following pathologic stages**.
** Gastric cancer "adenocarcinoma (general type)"; stage 0-I, colorectal cancer (adenocarcinoma); stage 0-I, rectal cancer (adenocarcinoma); stage 0-I, esophageal cancer (squamous cell carcinoma, adenosquamous cell carcinoma, basaloid cell carcinoma); stage 0, breast cancer (noninvasive ductal carcinoma, noninvasive lobular carcinoma); stage 0, breast cancer (invasive ductal carcinoma, invasive lobular carcinoma, Paget's disease); stages 0-IIA, uterine cancer (endometrial adenocarcinoma, mucinous adenocarcinoma); stage I, prostate cancer (adenocarcinoma); stages I-II, uterine cervical cancer (squamous cell carcinoma); stage 0, thyroid cancer (papillary carcinoma, follicular carcinoma); stage I-III, renal cancer (clear cell carcinoma, pigment cell carcinoma); stage I, other lesions equivalent to carcinoma in situ. Staging is based on UICC-TNM 7th edition or equivalent in principle.
13) Participating in a study or clinical trial of an unapproved drug or other research requiring intervention (Except during the follow-up period, after key openings, or in the placebo group).
14) Significant cardiovascular disease (New York Heart Association Class II or greater cardiac disease, myocardial infarction), unstable arrhythmias, or unstable angina within 90 days before enrollment.
15) Pregnant, breastfeeding, positive pregnancy test (all women who have experienced menstruation within the last year will be tested), or women and men who are unwilling to use contraception during the study.
16) History of hepatic encephalopathy.

Related Information

• Primary Sponsor: Masatoshi KUDO
• Secondary Sponsor: Chugai Pharmaceutical Co., Ltd.