Phase Ib trial of durvalumab plus tremelimumab in combination with particle radiotherapy in advanced hepatocellular carcinoma patients with macrovascular invasion: DEPARTURE trial.
Authors: Ogasawara Sadahisa , Koroki Keisuke , Makishima Hirokazu , Wakatsuki Masaru , Sakuma Takafumi , Fujita Naoto , Kanzaki Hiroaki , Kobayashi Kazufumi , Kiyono Soichiro , Nakamura Masato , Kanogawa Naoya , Saito Tomoko , Kondo Takayuki , Nakagawa Ryo , Nakamoto Shingo , Muroyama Ryosuke , Chiba Tetsuhiro , Hanaoka Hideki , Tsuji Hiroshi , Kato Naoya 
Published: January 2022

TPS495 Background: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all HCC cases, due to its uniqueness of disease condition. Development of revolutionary therapeutic approaches to improve prognosis in these patients is an essential medical issue. A phase I/II trial demonstrated that treatment with durvalumab, an anti-programmed death-ligand 1 antibody, alone or in combination with tremelimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, exhibited potential efficacy in patients with advanced HCC. Conversely, particle radiotherapy, including carbon-ion radiotherapy, has been shown to achieve unique dose distribution by delivering high-dose radiation to the target tumor while reducing the radiation dose to normal tissues due to its physical characteristics. Studies demonstrated that particle radiotherapy could achieve good local control in patients with HCC, including those with MVI. Additionally, particle radiotherapy as well as photon irradiation not only mediate localized tumor killing but also modify the tumor microenvironment, thereby potentiating the efficacy of immune checkpoint inhibitors. The DEPARTURE trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle radiotherapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI. Methods: This is a phase Ib, multi-center, open-label, single-arm, investigator-initiated clinical trial to assess the safety of durvalumab monotherapy in combination with particle radiotherapy (Cohort A) and that of durvalumab plus tremelimumab in combination with particle radiotherapy (Cohort B) in advanced HCC patients with MVI who are ineligible for standard systemic therapy and Child–Pugh A liver disease. Cohort A will receive 1500 mg durvalumab every four weeks in principle. Cohort B will receive 1500 mg durvalumab every four weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle, following the first dose of either durvalumab or durvalumab plus tremelimumab on day 1. Dose prescription and fractionations are 60 Gy (RBE) in four fractions/1 week. Intrahepatic nodule with MVI is the target lesion for carbon-ion radiotherapy. Primary study endpoints are rates of all and severe adverse events including DLTs. Secondary endpoints include rates of overall survival, 6-month survival, objective response, and 6-month progression-free survival as well as time to progression. Clinical trial information: jRCT2031210046.