Study of PD-1 Inhibitor in Combination With Gemcitabine/Cisplatin for Advancer BTCs

A Pilot Study of PD-1 Inhibitor in Combination With Gemcitabine/Cisplatin for Patients With Advanced Unresectable or Metastatic Biliary Tract Cancers

This is a single-arm, phase I/II trial in biliary tract cancer (BTC) patients. The purpose of this trial is to evaluate the safety and effect of PD-1 inhibitor in combination with gemcitabine/cisplatin chemotherapy in patients with advanced unresectable or metastatic BTCs.

The primary objective: 6-month progression free survival (PFS). The second objectives: objective clinical response(according to RECIST version 1.1), safety, symptom control and quality of life (QoL) (according to EORTC QoL C30 and BIL 21), overall survival. The exploratory objectives: assessment of immunological response (cytokines, lymphocyte phenotype, immunoglobulins), and evaluation of pathological, immunological and clinical predictive factors for response/toxicity.

Inclusion Criteria:

• Age≥18 years with estimated life expectancy >3 months.
• Histopathological/cytological diagnosis of unresectable or recurrent / metastatic biliary tract carcinoma (intra-hepatic, extrahepatic or gall bladder) and had at least one measurable disease (≥1cm) by CT or MRI.
• Patients should provide samples of tumor tissue biopsied or resected no more than 3 months before enrollment and be willing to accept biopsy in the process of the study.
• Patients may have received prior radiotherapy,chemotherapy,or other local ablative therapies, which completed ≥ 4 weeks prior to registration AND patient has recovered to <= grade 1 toxicity.
• ECOG (Eastern Cooperative Oncology Group) performance status of 0-2.
• Adequate organ and marrow function obtained ≤ 2 weeks prior to registration as defined below:

leukocytes greater than or equal to 3.0 x 10^9/L absolute neutrophil count greater than or equal to 1.0 x 10^9/L platelets greater than or equal to 100 x 10^9/L hemoglobin greater than or equal to 90 g/L total bilirubin less than or equal to 2 xULN serum albumin should be no less than 25g/L ALT or AST less than 2 xULN serum creatinine less than 1.5 x ULN

• Ability to understand and willingness to sign a written informed consent document.
• women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and up to 120 days after the last dose of the drug.

Exclusion Criteria:

• Active, known or suspected autoimmune diseases.
• Known brain metastases or active central nervous system (CNS). If patients with CNS metastases were treated with radiotherapy for at least 3 months prior to enrollment and have no central nervous symptoms and are off corticosteroids, they will be eligible but will need a Brain MRI prior to enrollment.
• Participants are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
• Prior therapy with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody (including ipilimumab or any other antibody specifically targeting T-cell costimulation or checkpoint pathways).
• History of severe hypersensitive reactions to other monoclonal antibodies.
• History of allergy or intolerance to study drug components.
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
• History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function.
• Uncontrolled intercurrent illness including ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient.
• History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
• Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented.
• Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
• Vaccination within 30 days of study enrollment.
• Active bleeding or known hemorrhagic tendency.
• Patients with unhealed surgical wounds for more than 30 days.
• Being participating any other trials or withdraw within 4 weeks.