First-line Treatment for Unresectable Locally Advanced Distal Cholangiocarcinoma Combining Radiotherapy and HAIC

A Single-arm, Exploratory Phase II Clinical Trial of Combined Radiotherapy and HAIC as First-line Treatment for Unresectable Locally Advanced Distal Cholangiocarcinoma

The median survival of intrahepatic cholangiocarcinoma remains less than one year, highlighting the need for new treatments. Hepatic arterial infusion chemotherapy (HAIC), especially with fluoropyrimidine-based regimens, has shown promise in ICC treatment due to increased local drug concentration and reduced systemic toxicity. A combined approach of radiotherapy and HAIC with gemcitabine infusion may offer a hopeful strategy for locally advanced cholangiocarcinoma. However, clinical research on this combination is lacking as first-line therapy for unresectable ICC. Therefore, a single-center, single-arm study aims to assess this treatment approach's safety, efficacy, and molecular predictors. Improved HAIC delivery through modified percutaneous implantation provides a reliable pathway for effective treatment. In conclusion, exploring the synergistic effects of radiotherapy and HAIC in ICC could pave the way for more effective and personalized treatment strategies for this challenging cancer type.

Intrahepatic cholangiocarcinoma (ICC) ranks as the second most common primary liver cancer, constituting 15%-20% of malignant liver tumors, with a rising incidence trend. Unlike hepatocellular carcinoma (HCC), ICC displays higher invasiveness and metastatic potential. Surgical resection remains the optimal treatment, yet many patients present with unresectable disease or metastasis, limiting surgical options. Chemotherapy, particularly the GC regimen, is standard for unresectable and metastatic ICC. Studies like ABC-02 have improved survival with GC chemotherapy compared to gemcitabine monotherapy. However, the median survival remains less than one year, highlighting the need for new treatments. Hepatic arterial infusion chemotherapy (HAIC), especially with fluoropyrimidine-based regimens, has shown promise in ICC treatment due to increased local drug concentration and reduced systemic toxicity. A combined approach of radiotherapy and HAIC with gemcitabine infusion may offer a hopeful strategy for locally advanced cholangiocarcinoma. However, clinical research on this combination is lacking as first-line therapy for unresectable ICC. Therefore, a single-center, single-arm study aims to assess this treatment approach's safety, efficacy, and molecular predictors. Improved HAIC delivery through modified percutaneous implantation provides a reliable pathway for effective treatment. In conclusion, exploring the synergistic effects of radiotherapy and HAIC in ICC could pave the way for more effective and personalized treatment strategies for this challenging cancer type.

Inclusion Criteria:

• 18-75 years, both male and female.
• Histologically or cytologically confirmed primary cholangiocarcinoma (including intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and gallbladder carcinoma) or imaging-confirmed localized cholangiocarcinoma, staged as T1-4N0/N+M0 (according to AJCC 7th edition clinical staging).
• Ineligible for surgical treatment or refusal of surgical treatment upon pre-treatment assessment.
• Presence of measurable lesions as per RECIST v1.1 criteria for evaluation.
• ECOG performance status: 0-1.
• Expected survival of more than 6 months.
• Tolerable function of major organs for treatment.
• Non-surgically sterilized or premenopausal female patients need to use a medically accepted contraceptive method during the study treatment period and within 3 months after the end of the study treatment.

Exclusion Criteria:

• Subjects with any active autoimmune disease or a history of autoimmune disease are excluded.

• Patients with poorly controlled clinical symptoms or diseases related to the heart, such as:

  1. NYHA Class 2 or above heart failure
  2. Unstable angina
  3. Myocardial infarction within the past year
  4. Clinically significant ventricular or supraventricular arrhythmias requiring treatment or intervention
  5. QTc >450 ms (males); QTc >470 ms (females)

• Abnormal coagulation function (INR >1.5 or PT >16s), bleeding tendencies, or receiving thrombolytic or anticoagulant therapy.

• Subjects who have received radiation therapy, chemotherapy, steroid therapy, surgery, or molecular targeted therapy within less than 4 weeks (or 5 half-lives of the drug, whichever is longer) before the study drug's first dose, or who have not recovered from adverse events caused by previous treatment (excluding alopecia) to ≤Grade 1 according to CTCAE.

• Subjects with clinically symptomatic ascites, pleural effusion, or pericardial effusion requiring therapeutic puncture or drainage. Those who have had stable ascites or effusion after drainage of pleural or pericardial effusion for at least 2 weeks before the first dose of the study drug can be included in the study.

• Subjects with significant hemoptysis in the last 2 months or hemoptysis of half a teaspoon (2.5 ml) or more.

• Known hereditary or acquired bleeding and thrombotic tendencies (such as hemophiliacs, coagulation disorders, thrombocytopenia, splenomegaly, etc.) or those who have had arterial or venous thrombotic events within the last 6 months (prior to first SHR-1210 administration).

• Subjects with active infections or unexplained fever >38.5°C during screening or before the first dose of the study drug.

• Patients with objective evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severe lung function impairment, etc., either historically or currently.

• Subjects with congenital or acquired immunodeficiency (such as HIV infection) or active hepatitis (HBV reference: HBV DNA test value exceeds the upper limit of normal; HCV reference: HCV virus titer or RNA test value exceeds the upper limit of normal).

• Use of other investigational drugs within 4 weeks prior to the first dose of the study drug.

• Subjects with a history of or concurrent other malignancies (excluding cured basal cell carcinoma and cervical carcinoma in situ).

• Subjects who may receive other systemic anti-tumor therapies during the study.

• Subjects who have previously received PD-1 antibody therapy or immune therapy targeting PD-1/PD-L1.

• Vaccination with live vaccines within less than 4 weeks before the study drug's administration or potentially during the study period.

• Other factors judged by the investigator that may necessitate premature termination of the study.