A Phase Ib/II Clinical Trial Evaluating the Safety and Efficacy of Atezolizumab Plus Bevacizumab Combination Therapy as Adjuvant Treatment After Carbon Ion Radiotherapy for Hepatocellular Carcinoma

JRCT ID: jRCT2031240284

Registered date:20/08/2024

Basic Information

• Recruitment status: Pending
• Health condition(s) or Problem(s) studied: hepatocellular carcinoma
• Date of first enrollment: 30/08/2024
• Target sample size: 48
• Study type: Interventional

Intervention(s)

[Carbon Ion Radiotherapy (CIRT)]
Carbon Ion Radiotherapy (CIRT) is performed for 4 consecutive operating days (in principle within 1 week, and in the event of postponement of irradiation, the treatment is completed within 2 weeks).

[Atezolizumab]
Within 42 days of the start of Carbon Ion Radiotherapy (CIRT), 1200 mg of Atezolizumab is administered intravenously once every 3 weeks.

[Bevacizumab]
Within 42 days of the start of Carbon Ion Radiotherapy (CIRT), 15mg/kg of Bevacizumab is administered intravenously once every 3 weeks.

Outcome(s)

Primary Outcome

[phase Ib]
Ratio of DLTs

[phase II]
1-year recurrence-free survival

Secondary Outcome

[phase Ib]
<Secondary safety endpoints>
Ratio of adverse events/serious adverse events
<Secondary efficacy endpoints>
1-year recurrence-free survival (1y-RFS), overall survival (OS), 6-month survival

[phase II]
2-year recurrence-free survival (2y-RFS), overall survival (OS), 6-month survival

Key inclusion & exclusion criteria

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

Include criteria

Primary Enrollment
1) Patients who are at least 18 years of age at the time of consent
2) Patients with primary hepatocellular carcinoma
3) Patients with an ECOG PS of 0 or 1
4) Patients who meet the following criteria in laboratory tests
1)Hemoglobin >= 9.0 g/dL
2) Neutrophil count >= 1,500/mm3
3) Platelet count >= 60,000/mm3
4) AST <= 5 x ULN
5) ALT <= 5 x ULN
6) Total bilirubin <= 3.0 x ULN
7) Creatinine <= 1.5 x ULN
8) Urinary protein less than 2+.
In case of 2+ or more, urinary protein/creatinine ratio in urine at any time: less than 1.0
5) Patients with Child-Pugh Classification A at the time of enrollment
6) Patients expected to be alive for at least 12 weeks at the time of enrollment
7) Patients diagnosed with hepatocellular carcinoma with histologically or radiologically typical contrast pattern*1 prior to heavy ion therapy
*1: A typical contrast pattern is defined as a high absorption (high signal) area in the arterial phase of contrast CT or contrast-enhanced MRI scan and a relatively low absorption (low signal) area (washout) in the portal vein/equilibrium phase compared to the surrounding liver parenchyma.
8) Patients who are judged to be amenable to curative treatment with heavy-ion radiation therapy.
9) Patients with a maximum intrahepatic tumor diameter of 4 cm or greater
10) Patients with 3 or fewer intrahepatic tumors
11) Patients confirmed to have no severe portal vein invasion (Vp3 or Vp4) or any degree of invasion into the hepatic vein or inferior vena cava.
12) Patients confirmed free of extrahepatic metastases by CT or MRI scan of the chest, abdomen, or pelvis
13) Patients who have received a full explanation of the contents of the explanatory document and other matters related to the clinical trial, understand the contents of the explanatory document, and have given their free and voluntary written consent to participate in this clinical trial.

Secondary Enrollment
1) Patients who have completed heavy particle irradiation* and have been irradiated for at least 14 days.
*4 heavy particle irradiation within the period specified in the study protocol.
2) Patients with an ECOG-PS of 0 or 1 confirmed at the secondary screening.
3) Patients with a Child-Pugh classification of Class A at the time of secondary screening
4) Patients who meet the following criteria in the laboratory tests performed at the time of secondary screening
1) Hemoglobin >= 9.0 g/dL
2) Neutrophil count >= 1,500/mm3
3) Platelet count >= 60,000/mm3
4) AST <= 5 x ULN
5) ALT <= 5 x ULN
6) Total bilirubin <= 3.0 x ULN
7) Creatinine <= 1.5 x ULN
8) Urinary protein less than 2+.
In case of 2+ or more, urinary protein/creatinine ratio in urine at any time: less than 1.0
5) Patients with no new intrahepatic lesions or extrahepatic metastases confirmed by chest, abdomen, pelvic region and CT or MRI scan

Exclude criteria

Primary Enrollment
1) Patients participating in another clinical trial using an investigational drug within 28 days prior to obtaining consent
2) Patients who received radiotherapy within 4 weeks prior to enrollment
3) Patients with a history of allogeneic organ transplantation
4) Patients with active overlapping cancers. However, duplicate cancers that do not have a defined prognosis and do not require active treatment, such as early-stage cancer, are acceptable.
5) Patients with infectious diseases (except viral hepatitis) that have systemic treatment
6) Patients with a history of active primary immunodeficiency
7) Women who are pregnant, possibly pregnant, or lactating. Patients who are pregnant or lactating.
Male patients who wish to carry their partner to term.
8) Patients with psychiatric disorders or concomitant psychiatric symptoms that interfere with daily life or are judged to be incompetent to give their consent, making it difficult for them to participate in the study.
9) Patients receiving continuous systemic administration of steroids (prednisone equivalent > 10 mg/day) or other immunosuppressive drugs for the treatment of autoimmune or other diseases
10) Patients taking antiplatelet or anticoagulant drugs for therapeutic (not prophylactic) purposes
11) Patients with a history of hepatic encephalopathy within 3 months prior to enrollment (including the same date 3 months prior to enrollment)
12) Patients with a history of rupture of esophageal or gastric varices or with esophageal or gastric varices with bleeding risk (Form >=F2 or RC sign based on the 3rd edition of the Japanese Code of Medical Practice for Portal Hypertension) on upper gastrointestinal endoscopy within 6 months prior to enrollment (including the same date 6 months prior to the date of enrollment) Patients with esophageal or gastric varices with a risk of bleeding on portal hypertension. Patients who have been treated prophylactically for esophageal or gastric varices by the standard methods of the implementing institution prior to enrollment and are judged not to be at risk for bleeding may be enrolled.
13) Patients with interstitial pneumonia, pulmonary fibrosis, or severe emphysema, as diagnosed by imaging studies (chest X-ray, CT), or with one or more complications.
14) Patients with serious complications (heart failure, renal failure, liver failure, intestinal paralysis, intestinal obstruction)
15) Patients complicated with poorly controlled hypertension or poorly controlled diabetes mellitus (patients may be enrolled if they are controllable prior to enrollment).
16) Patients with unstable angina pectoris or a history of myocardial infarction within 6 months prior to enrollment.
17) Patients who have received treatment for blood (including blood transfusions, blood products or hematopoietic factor products such as G-CSF) within 14 days prior to enrollment
18) Patients with a history of radiation therapy with liver effects prior to enrollment
19) Patients with a history of hypersensitivity to any component of the investigational drug
20) Patients with conditions that are contraindicated in the package insert.
21) Patients who are judged by the investigator or subinvestigator to be inappropriate for this study.

Secondary Enrollment
1) Patients with radiation lung injury due to heavy particle irradiation that does not recover to Grade 1 or below
2) Patients with gastrointestinal disorders associated with heavy particle irradiation that do not recover to Grade 1 or below.
3) Patients with radiation dermatitis associated with heavy particle irradiation that does not recover to Grade 1 or less
4) Patients who are judged by the investigator or subinvestigator to be inappropriate for this clinical trial.

Related Information

• Primary Sponsor: Ogasawara Sadahisa
• Source(s) of Monetary Support: Chugai Pharmaceutical Co., Ltd.,Chiba University Hospital