Study of Nivolumab in Patients With Advanced Refractory Biliary Tract Cancers

Study Overview
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Brief Summary
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This research study is designed to see if a drug called Nivolumab is effective in treating patients with advanced refractory biliary tract cancers. Nivolumab has been approved by the U.S. Food and Drug Administration (FDA) for treatment of certain types of cancer but is not approved by the FDA for treatment of your type of cancer.

Official Title
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A Phase II Investigator Sponsored Study of Nivolumab in Patients With Advanced Refractory Biliary Tract Cancers

Conditions
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Biliary Tract Cancer, Biliary Tract Neoplasms

Intervention / Treatment
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* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Must have failed or are intolerant to one line of systemic treatment but no more than 2 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. Age ≥ 18 Eastern Cooperative Oncology Group (ECOG) Performance Status Assessment of 0 or 1. Must have radiographic measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. 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. Must be able to understand and be willing to sign the written informed consent form. 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 NCI-CTCAE v4.0 Grade 1 or less at the time of signing the Informed Consent Form (ICF) except for alopecia. Adequate bone marrow, liver and liver function. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity of 25 IU/L or equivalent units of HCG) performed within24 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. 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. 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 (FFPE block or cell block will be required). Exclusion Criteria: Active central nervous system (CNS). If CNS metastases are treated and potential participants are at neurologic baseline for at least 2 weeks prior to enrollment, they will be eligible but will need a Brain MRI prior to enrollment. Must be off corticosteroids or on a dose of less than 10 mg per day. Active, known or suspected autoimmune disease. Potential participants 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. 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 grade1 attributed to any prior therapy/procedure excluding alopecia. Pregnant or breast-feeding patients. Women of childbearing potential must have a negative serum or urine 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 results 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. Excluded Therapies and Medications for Cancer: 1) Anticancer chemotherapy during the study or within 4 weeks of study enrollment. Must have recovered from the toxic effects of the previous anti-cancer chemotherapy (with the exception of alopecia). Anti-cancer therapy is defined as any agent or combination of agents with clinically proven anti-tumor activity administered by any route with the purpose of affecting the malignancy, either directly or indirectly, including palliative and therapeutic endpoints. 2) Hormonal therapy during the study or within 2 weeks of first study enrollment. 3) Radiotherapy to target lesions during study or within 2 weeks of enrollment. 4) An irradiated lesion is considered evaluable only if it has shown enlargement since the completion of last radiation. 5) Bone marrow transplant or stem cell rescue. 6) Investigational drug therapy outside of this trial during or within 4 weeks of first study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab Treatment<br>This is a single arm study with two stage design using nivolumab in advanced biliary tract cancer (BTC), for participants who have failed or are intolerant to at least one line of therapy and no more than 2 lines of therapy. In the first stage, 18 participants will be accrued. If there is at least one response (or several participants with stable disease based on the study team's discretion), an additional 34 patients will be accrued for a total of 52 patients. | Drug: Nivolumab<br>* Participants will receive nivolumab at a dose of 240 mg intravenously (IV) every 2 weeks (Q 2W) for 16 weeks (16W) and then 480 every 4 weeks (Q4W) from 17 weeks to end of study.<br>* Other names: OPDIVO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) After 4 Cycles of Treatment | Response in participants with advanced biliary tract cancers receiving nivolumab as a single agent. ORR is defined as complete responses (CR) plus partial responses (PR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from enrollment to the date of death. | Up to 36 months | 
| Progression Free Survival (PFS) | PFS is defined as the time from first treatment to the date of the first documented tumor progression as determined by the investigator (per RECIST 1.1), or death due to any cause. | Up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced biliary tract cancer, refractory biliary tract cancer, digestive diseases, immunotherapy