This is a prospective, Two-arm, comparative, randomized, controlled phase II trial, to explore the efficacy and safety of Regorafenib and HAIC vs. FOLFOX as Second Line Therapy for Advanced Intrahepatic Cholangiocarcinoma.

Currently, complete surgical resection represents the only potentially curative treatment option for cholangiocarcinoma (CCA, including intrahepatic, hilar and distal CCA) and gallbladder carcinoma (GBCA). However,only less than 25% of patients are resectable at diagnosis and, even in this subset of patients, relapse rate is high.

Cisplatin and gemcitabine combination was identified as the standard first-line chemotherapy, yielding a median progression free survival (PFS) and median OS of 8.5 and 11.7 months, respectively. FOLFOX was the standard second-line chemotherapy. But the benefit of FOLFOX was limited.

Inclusion Criteria:

• Signed and dated IRB/IEC-approved Informed Consent.
• Cytological or histological diagnosis of locally advanced or metastatic adenocarcinoma of the Intrahepatic Cholangiocarcinoma.
• Disease progressing after first-line chemotherapy with gemcitabine and platinum analogs (only one prior systemic therapy allowed).
• Age 18-75 years
• Karnofsky Performance Status > 50%
• Estimated life expectancy of at least 3 months.
• Negative pregnancy test (if female in reproductive years).
• Adequate bone marrow, liver and kidney function: leukocyte > 3500/mm3; absolute neutrophil count (ANC) > 1500/mm3; platelet count > 100000/mm3; hemoglobin > 10 g/dl; creatinine < 1.5 mg/dL; total bilirubin ≤ 1.5 x upper limit of normal range (ULN); SGOT e SGPT ≤ 2.5 ULN
• At the time of start of treatment, at least 2 weeks must have elapsed since completion of prior chemotherapy, minor surgery and radiotherapy (provided that no more than 25% of bone marrow reserve has been irradiated).
• Resolution of all acute toxic effects of any prior chemotherapy, surgery or radiotherapy to NCI CTC (Version 4.03) grade ≤ 1 for hematologic toxicities and ≤ 2 for non hematologic toxicities, with the exception of alopecia.
• Able and willing to comply with scheduled visits, therapy plans, and laboratory tests required in this protocol.

Exclusion Criteria:

• History of cardiac disease
• Ongoing infection > Grade 2 according to NCI-CTCAE version 4.03. Hepatitis B is allowed if no active replication (defined as abnormal ALT >2xULN associated with HBV DNA >20,000 IU/mL) is present
• Severe co-morbid illness and/or active infections including active hepatitis C and human immunodeficiency virus (HIV) infection
• History of interstitial lung disease (ILD).
• Any cancer curatively treated < 3 years prior to study entry, except cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors (Staging: Ta, Tis and T1).
• Renal failure requiring hemo- or peritoneal dialysis.
• Clinically significant GI bleeding (CTCAE 4.03 grade 3 or higher) within 30 days prior to start of screening
• Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months prior to start of screening.
• History of organ allograft, cornea transplantation will be allowed
• Active CNS metastases not controllable with radiotherapy or corticosteroids Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for RVO or CSR.
• Known history of hypersensitivity to study drugs
• Non-healing wound, ulcer, or bone fracture.
• Patients with seizure disorder requiring medication.
• Acute steroid therapy or taper for any purpose (chronic steroid therapy is acceptable provided that the dose is stable for 1 month before start of screening and thereafter).
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
• Pregnant or lactating women. Women of childbearing potential not employing adequate contraception. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to start of study treatment and a negative result must be documented before first dose of study drug.