Pembrolizumab, a Monoclonal Antibody Against PD-1, in Combination With Capecitabine and Oxaliplatin (CAPOX) in People With Advanced Biliary Tract Carcinoma (BTC)

Study Overview
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Brief Summary
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Background: Biliary tract cancers are rare but they are serious. Researchers want to see if a certain drug helps the immune system fight cancer cells. The drug is called pembrolizumab. It may work even better with two chemotherapy drugs that are widely used to treat gastrointestinal cancers. Objective: To study if pembrolizumab given with capecitabine and oxaliplatin (CAPOX) increases the time it takes for a person's biliary tract cancer to get worse. Eligibility: People age 18 and older with previously treated biliary tract cancer that has spread to other parts of the body Design: Participants will be screened with tests as part of their regular cancer care. Each study cycle is 3 weeks. For 6 cycles, participants will: Get pembrolizumab and oxaliplatin on day 1 of each cycle. They will be given in an intravenous (IV) catheter. Take capecitabine by mouth for 2 weeks then have 1 week without it. Participants will complete a patient diary. Starting with cycle 7, participants will get only pembrolizumab. They will get it once every 3 weeks. On day 1 of every cycle, participants will have: Physical exam Review of symptoms and how well they do normal activities Blood tests Every 9 weeks, they will have a scan. Participants may have tumor samples taken. Participants will have a final visit about 1 month after they stop the study drug. After that, they will be contacted by phone or email yearly.

Detailed Description
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Background: The most compelling argument in favor of testing immune-based strategies (and anti-Programmed cell death protein 1 (PD1) therapy in particular) in biliary tract cancers (BTC) is that chronic inflammation appears to be the most common etiologic factor in the development of biliary tract cancer. Single-agent activity has been shown for PD1-directed therapy in BTC. Given the potential for oxaliplatin-induced immunogenic cell death we would like to evaluate the combination of capecitabine and oxaliplatin (CAPOX) chemotherapy with pembrolizumab. Objective: To determine the 5-month progression free survival (PFS) of Pembrolizumab in combination with CAPOX in patients with advanced biliary tract carcinoma. Eligibility: Histologically confirmed diagnosis biliary tract carcinoma OR histopathological confirmation of carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of biliary tract carcinoma. Patients must have at least one prior chemotherapeutic regimen. Patients must have disease that is not amenable to potentially curative resection. No prior treatment with oxaliplatin. Design: The proposed study is a phase II study of Pembrolizumab in combination with CAPOX in patients with advanced biliary tract carcinoma

Official Title
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A Phase 2 Study of Pembrolizumab, a Monoclonal Antibody Against PD-1, in Combination With Capecitabine and Oxaliplatin (CAPOX) in Subjects With Advanced Biliary Tract Carcinoma (BTC)

Conditions
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Biliary Tract Neoplasms, Cholangiocarcinoma, Bile Duct Cancer, Liver Cancer, Gallbladder Cancer

Intervention / Treatment
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* Biological: Pembrolizumab (MK-3475)
* Drug: Oxaliplatin
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have histopathological confirmation of biliary tract carcinoma (BTC) by the Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this study OR histopathological confirmation of carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of biliary tract carcinoma. The term BTC includes intra- or extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer. Patients must have disease that is not amenable to potentially curative resection. Patients must have received, been intolerant of or refused at least one line of chemotherapy. Patients must have at least one focus of measurable metastatic disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsies. Ideally the biopsied lesion should not be one of the target measurable lesions, although this can be up to the discretion of the investigators. Age greater than or equal to 18 years Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Patients must have normal organ and marrow function as defined below: leukocytes greater than or equal to 3,000/mcL absolute neutrophil count greater than or equal to 1,000/mcL platelets greater than or equal to 100,000/mcL total bilirubin less than or equal to 2 xULN Serum albumin greater than or equal to 2.5g/dl Patients are eligible with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) up to 5 x upper limit of normal (ULN). creatinine <1.5X institution upper limit of normal OR creatinine clearance greater than or equal to 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 or returned to baseline. Patients must not have other invasive malignancies within the past 5 years (with the exception of non-melanoma skin cancers, non-invasive bladder cancer or localized prostate cancer for whom systemic therapy is not required). Patient must be able to understand and willing to sign a written informed consent document. The effects of Pembrolizumab in combination with Capecitabine and Oxaliplatin on the developing human fetus are unknown. For this reason, 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, for the duration of study participation and up to 120 days after the last dose of the drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. EXCLUSION CRITERIA: Patients who have had standard of care chemotherapy, large field radiotherapy, or major surgery must wait 2 weeks prior to entering the study. Previous treatment with immune checkpoint inhibitors. Patients who have undergone prior liver transplantation are ineligible. Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Uncontrolled intercurrent illness including, but not limited to, 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 that would limit compliance with study requirements. History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis. History of chronic autoimmune disease (e.g., Addison s disease, multiple sclerosis, Graves disease, Hashimoto's thyroiditis, rheumatoid arthritis, hypophysitis, etc.) with symptomatic disease within the 3 years before randomization. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion. Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requirements of the protocol Active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener's granulomatosis. Currently receiving immunosuppressive doses of steroids or other immunosuppressive medications (inhaled and topical steroids are permitted) History of sarcoidosis syndrome. Known history of active tuberculosis. Patients should not be vaccinated with live attenuated vaccines within 1 month of starting pembrolizumab treatment. Active hepatitis B or C infection. Human Immunodeficiency Virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and pembrolizumab. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that pembrolizumab may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events. History of hypersensitivity reaction to human or mouse antibody products. Female patients who are pregnant or breastfeeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Pembrolizumab in combination with Capecitabine and Oxaliplatin, breastfeeding should be discontinued. Patients with unhealed surgical wounds for more than 30 days. Prior therapy with oxaliplatin

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: 1/Arm 1<br>Pembrolizumab plus Oxaliplatin plus Capecitabine | Biological: Pembrolizumab (MK-3475)<br>* 200 mg will be administered as an IV infusion on Day 1 of each 21 day cycle<br>Drug: Oxaliplatin<br>* 130mg/m(2) IV Infusion will be administered as an IV infusion on Day 1 of cycles 1-6<br>Drug: Capecitabine<br>* 750 mg/m(2) will be administered orally twice a day on Days 1-14 of cycles 1-6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Median amount of time subject survives without disease progression for 5 months after treatment. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions. | 5 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Obtaining a Complete Response (CR) and Partial Response (PR) | Number of participants obtaining CR and PR per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria of all evaluable patients. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions,taking as reference the baseline sum of diameters. | Every 9 Weeks, until disease progression or patient is taken off the trial, whichever comes first, approximately 36 weeks. | 
| Overall Survival | Median amount of time subject survives after therapy. | Death, approximately 48 weeks after stopping therapy. | 
| Number Participants With Grade 1-4 Adverse Events Unrelated, Unlikely, Possibly, Probably and Definitely Related to Pembrolizumab | Here is the number of participants with grade 1-4 adverse events unrelated, unlikely, possibly, probably and definitely related to study drug assessed by the Common Terminology Criteria for Adverse Events v4.0. Mild (Grade1), moderate (Grade 2), severe (Grade 3), and life-threatening or disabling (Grade 4). | 30 Days After Enrollment | 
| Number Participants With Grade 1-4 Adverse Events Unrelated, Unlikely, Possibly, Probably and Definitely Related to Oxaliplatin | Here is the number of participants with grade 1-4 adverse events unrelated, unlikely, possibly, probably and definitely related to study drug assessed by the Common Terminology Criteria for Adverse Events v4.0. Mild (Grade1), moderate (Grade 2), severe (Grade 3), and life-threatening or disabling (Grade 4). | 30 Days After Enrollment | 
| Number of Participants With Grade 1-4 Adverse Events Unrelated, Unlikely, Possibly, and Probably Related to Capecitabine | Here is the number of participants with grade 1-4 adverse events unrelated, unlikely, possibly, and probably related to study drug assessed by the Common Terminology Criteria for Adverse Events v4.0. Mild (Grade1), moderate (Grade 2), severe (Grade 3), and life-threatening or disabling (Grade 4). | 30 Days After Enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune-Based Strategies, Anti-PD1 Therapy, Chronic Inflammation, Combination Chemotherapy