Study of Nivolumab in Patients with Advanced Refractory Biliary Tract Cancers

Inclusion Criteria

• Patients must have histologically or cytologically documented carcinoma primary to the intra- or extra-hepatic biliary system or gall bladder with clinical and/or radiologic evidence of unresectable, locally advanced or metastatic disease; patients with ampullary carcinoma are not eligible
• Patients must have failed or are intolerant to one line of systemic treatment but no more than 3 prior lines of systemic chemotherapy for advanced BTC; patients who received adjuvant chemotherapy and had evidence of disease recurrence within 6 months of completion of the adjuvant treatment are also eligible; if the patient received adjuvant treatment and had disease recurrence after 6 months, patients will only be eligible after failing or having intolerance to one line of systemic chemotherapy used to treat the disease recurrence
• Eastern Cooperative Oncology Group (ECOG) performance status assessment of 0 or 1
• The patient must have radiographic measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• Life expectancy of at least 12 weeks (3 months)
• For patients who have received prior radiation, cryotherapy, radiofrequency ablation, TheraSphere, ethanol injection, transarterial chemoembolization (TACE) or photodynamic therapy, the following criteria must be met: * 28 days have elapsed since that therapy * Lesions that have not been treated with local therapy must be present and measureable
• Subjects must be able to understand and be willing to sign the written informed consent form; a signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure; subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other study requirements
• All acute toxic effects of any prior treatment have resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v) 4.0 grade 1 or less at the time of signing the informed consent form (ICF) except for alopecia
• Total bilirubin =< 1.5 x the upper limits of normal (ULN), except for subjects with Gilbert Syndrome who can have bilirubin < 3
• Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer or stent placement)
• Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)
• Serum creatinine < 2 x ULN
• Platelet count >= 100,000 /mm^3
• Hemoglobin (Hb) >= 9 g/dL
• Absolute neutrophil count (ANC) >= 1000/mm^3
• Blood transfusion to meet the inclusion criteria will be allowed
• Women of childbearing potential must have a negative serum pregnancy test (minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) performed within 24 hours prior to the start of nivolumab; post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test
• Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 3 months after the last dose of study drug; the definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate
• Patients with history of hepatitis B and hepatitis C will be eligible but patients with hepatitis B must be started on antiviral therapy prior to beginning study therapy
• Availability of archival tumor tissue for biomarkers analysis (formalin-fixed paraffin-embedded [FFPE] block or cell block will be required); specimen from primary site will be allowed; patients must have at least 10 slides available; repeat biopsy to obtain sufficient tissue for 10 slides is allowed

Exclusion Criteria

• Subjects with active central nervous system (CNS) metastases are excluded; if CNS metastases are treated and subjects are at neurologic baseline for at least 2 weeks prior to enrollment, they will be eligible but will need a brain magnetic resonance imaging (MRI) prior to enrollment; subjects must be off corticosteroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent)
• Subjects with active, known or suspected autoimmune disease; subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment; inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways)
• 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])
• Known history of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)
• Child Pugh B or C disease
• History of severe hypersensitivity reactions to other monoclonal antibodies
• History of allergy or intolerance to study drug components or polysorbate-80-containing infusions
• 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
• Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy/procedure excluding alopecia
• Pregnant or breast-feeding patients; women of childbearing potential must have a pregnancy test (minimum sensitivity of 25 IU/L or equivalent units of HCG) performed within 24 hours prior to the start of nivolumab, and a negative result must be documented before start of treatment
• Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study