Toripalimab Plus Lenvatinib and Gemcitabine-based Chemotherapy in 1L Treatment of Advanced ICC: a Phase III Study

Inclusion criteria

• Age of 18-75 years (inclusive), male or female;
• Volunteer to participate in the study by signing the informed consent form and the ability to comply with the study protocol;
• Advanced ICC with diagnosis confirmed by histology or cytology;
• Stage II, III, or IV per TNM staging for ICC of the American Joint Committee on Cancer (AJCC) (8th edition, 2017). Those with Stage II or III should be determined to be unresectable by the investigator;
• Patients with no prior systemic chemotherapy or targeted therapy or loco-regional therapy (including but not limited to transarterial chemoembolization, transarterial embolization, transarterial chemotherapy or transarterial radioembolization) for ICC. Patients with recurrent disease more than 6 months after completion of adjuvant chemotherapy following curative resection are eligible;
• Measurable lesion per RECIST v1.1;
• Child-Pugh class A with no history of hepatic encephalopathy;
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1;
• Life expectancy ≥12 weeks;

Exclusion criteria

• Diagnosis of hepatocellular carcinoma (HCC), mixed cholangiocarcinoma and HCC, sarcomatoid hepatocellular carcinoma, or hepatic fibrolamellar carcinoma by histology or cytology;
• History of malignancy other than ICC within 5 years prior to screening, with the exception of localized malignancies that have been cured, including non-melanoma skin cancers, cervical carcinoma in situ, breast carcinoma in situ, and papillary thyroid carcinoma;
• Prior radiotherapy for ICC within 4 weeks prior to randomization;
• Major surgical procedures within 4 weeks prior to randomization;
• Side effects from prior therapy (except alopecia and pigmentation) that has not recovered to ≤ grade 1 (per NCI-CTCAE v5.0) or levels specified in the inclusion/exclusion criteria;
• Uncontrolled pericardial effusion, pleural effusion, or clinically significant moderate or severe ascites that is symptomatic or requires thoracentesis or paracentesis during the screening phase for control of symptoms;
• Gastrointestinal (GI) hemorrhage within 6 months prior to randomization and/or gastrointestinal varices that have not been assessed and treated, if appropriate, within 6 months prior to randomization.
• Gastrointestinal or non-gastrointestinal fistula, gastrointestinal perforation, or abdominal abscess within 6 months prior to randomization;
• Ongoing or a history of recurrent intestinal obstruction. Patients with a single episode of intestinal obstruction that has fully resolved following treatment are eligible allowed;
• History of serious cardiovascular and cerebrovascular diseases:
• Significant bleeding and coagulopathy or other evidence of bleeding diathesis, to include:
• Pre-existing CNS metastases and/or meningeal metastases (including dural metastases and leptomeningeal metastases);
• Serious non-healing wound, active ulcer, or untreated bone fracture;
• Vaccination with live virus or bacteria within 30 days prior to randomization;
• Active autoimmune disease or history of autoimmune disease