{
  "abstract": "Introduction The establishment of an effective strategy for recurrence prevention following curative treatment for hepatocellular carcinoma (HCC), including radiotherapy, remains a critical unmet clinical need. Despite favourable local control and safety profiles, recurrence after particle therapy remains a major challenge, highlighting the need for effective adjuvant strategies to improve long-term outcomes. The present phase Ib/II trial is designed to evaluate the safety and efficacy of atezolizumab plus bevacizumab (Atezo+Bev) administered after carbon-ion radiotherapy (C-ion RT) in patients with unresectable non-metastatic large HCC. This study aims to explore the potential of this multimodal approach as a novel adjuvant strategy to improve outcomes in patients at high risk of recurrence.Methods and analysis This is a phase Ib/II, single-arm clinical trial designed to evaluate the safety and efficacy of adjuvant Atezo+Bev following C-ion RT in patients with HCC. Eligible patients will be enrolled in the first registration phase. C-ion RT (60 Gy) will be administered over four consecutive treatment days ideally within one calendar week. Patients will receive a combination of atezolizumab (1200 mg) and bevacizumab (15 mg/kg) administered intravenously every 21 days for one treatment cycle. The primary endpoint of the phase Ib part is the proportion of patients with dose-limiting toxicity (DLT). DLT is defined as prespecified toxicities associated with the investigational drug among the adverse events that occurred from the start date of the investigational drug (Day 1) to Day 21. If there is one or fewer cases of DLT out of six cases, the trial will proceed to the phase II part. The primary endpoint of the phase II part is the 1-year recurrence-free survival rate.Ethics and dissemination This study was approved by the ethics committee of two participating institutions (Chiba University Hospital (approval No. 2024021) and National Institute for Quantum and Radiological Science and Technology, QST Hospital (approval No. C24-001)). Trial results will be reported in a peer-reviewed journal publication.Trial registration number jRCT2031240284.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Keisuke Koroki"
    },
    {
      "affiliations": [
        "QST Hospital, National Institutes for Quantum Science and Technology, Chiba, Japan"
      ],
      "name": "Masaru Wakatsuki"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Sadahisa Ogasawara"
    },
    {
      "affiliations": [
        "QST Hospital, National Institutes for Quantum Science and Technology, Chiba, Japan"
      ],
      "name": "Hirokazu Makishima"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Taro Watabe"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Haruka Anzai"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Makoto Fujiya"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Midori Sawada"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Takahiro Tsuchiya"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Keiichi Katayama"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Ryohei Yoshino"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Ryo Izai"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Teppei Akatsuka"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Chihiro Miwa"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Takuya Yonemoto"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Sae Yumita"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Masanori Inoue"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Masato Nakamura"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Naoya Kanogawa"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Shingo Nakamoto"
    },
    {
      "affiliations": [
        "Clinical Research Center, Chiba University Hospital, Chiba, Japan"
      ],
      "name": "Kohei Takahashi"
    },
    {
      "affiliations": [
        "Clinical Research Center, Chiba University Hospital, Chiba, Japan"
      ],
      "name": "Yoshihito Ozawa"
    },
    {
      "affiliations": [
        "Clinical Research Center, Chiba University Hospital, Chiba, Japan"
      ],
      "name": "Yosuke Inaba"
    },
    {
      "affiliations": [
        "Clinical Research Center, Chiba University Hospital, Chiba, Japan"
      ],
      "name": "Tomoya Kurokawa"
    },
    {
      "affiliations": [
        "QST Hospital, National Institutes for Quantum Science and Technology, Chiba, Japan"
      ],
      "name": "Tetsuro Isozaki"
    },
    {
      "affiliations": [
        "Clinical Research Center, Chiba University Hospital, Chiba, Japan"
      ],
      "name": "Asahi Takahashi"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Jun Kato"
    },
    {
      "affiliations": [
        "Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan"
      ],
      "name": "Masayuki Ohtsuka"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, Gunma University School of Medicine, Gunma, Japan"
      ],
      "name": "Tatsuya Ohno"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Yamagata University School of Medicine, Yamagata, Japan"
      ],
      "name": "Yoshiyuki Ueno"
    },
    {
      "affiliations": [
        "Kanagawa Cancer Center, Yokohama, Japan"
      ],
      "name": "Junji Furuse"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan"
      ],
      "name": "Masatoshi Kudo"
    },
    {
      "affiliations": [
        "Clinical Research Center, Chiba University Hospital, Chiba, Japan"
      ],
      "name": "Hideki Hanaoka"
    },
    {
      "affiliations": [
        "QST Hospital, National Institutes for Quantum Science and Technology, Chiba, Japan"
      ],
      "name": "Hitoshi Ishikawa"
    }
  ],
  "title": "Phase Ib/II trial to evaluate the safety and efficacy of atezolizumab and bevacizumab as adjuvant therapy following carbon-ion radiotherapy in hepatocellular carcinoma (VANGUARD): study protocol",
  "uid": "d42910da-05a3-5af4-9a57-6cbbfcae337e"
}