Camrelizumab Combined With Apatinib and Capecitabine in Patients With Advanced Unresectable Biliary Tract Cancer.

Study Overview
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Brief Summary
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Biliary tract cancer (BTC) is a series of rare malignancies with poor overall prognosis. Radical surgery the preferred treatment option, but most patients have lost the opportunity of surgery at the time of diagnosis. At present, there are limited systematical treatment options for biliary tract cancer, with poor efficacy and short duration of responses. In the past few years, immune checkpoint inhibitors (ICIs) therapy has gradually been added to the advanced biliary comprehensive treatment. However, in view of the low incidence and high heterogeneity of BTC, more large number of clinical trials and practices need to be carried out, and the effective combination regimens and predictive biomarkers need to be explored. This study is a single-arm, open-label, prospective cohort study, combining Camrelizumab with apatinib and capecitabine as the first-line or second-line treatment for patients with advanced biliary tract cancer. The study aims to explore the efficacy and safety of the combination regimen, and try to find biomarkers that can guild treatment. In this study, 34 patients were enrolled by the Simon's two-stage design, with the objective response rate as the primary endpoint and the disease control rate, progression-free survival, overall survival and safety as secondary endpoints. It is expected that the three-drug combination regimen will have significant efficacy and manageable adverse reactions, and predictive biomarkers can be found.

Official Title
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Camrelizumab Combined With Apatinib and Capecitabine for Patients With Advanced Unresectable Biliary Tract Cancer: a Phase 2, Single-arm, Prospective Study.

Conditions
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Biliary Tract Cancer, Programmed Cell Death 1 Ligand 1 Gene Mutation, Targeted Molecular Therapy, Capecitabine

Intervention / Treatment
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* Drug: Camrelizumab
* Drug: apatinib
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-70 years old, both genders. Conform to the histological or cytological confirmation of biliary tract carcinoma，including gallbladder cancers and cholangiocarcinomas. Patients have advanced unresectable biliary tract carcinoma, including recurrence or metastasis of BTC after radical resection. Patientss who have not received any prior PD-1 inhibitor and Apatinib therapy. Patients must have at least 1 lesion that is measurable using RECIST v1.1 criteria. Eastern Cooperative Oncology Group Performance Status of 0 or 1within one week before enrollment. Life expectancy greater than 3 months. Patient must have adequate organ function defined by the study-specified laboratory tests. Patient must use acceptable form of birth control while on study. Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria: Patients with known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation or planned transplantation. Patients with other malignant tumor in the past 5 years (except cured skin basal cell carcinoma and cervical carcinoma). History of esophageal variceal bleeding, hepatic encephalopathy, massive ascites and abdominal infection. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids. Doses > 10 mg/day prednisone or equivalent are prohibited within 14 days before study drug administration. Known history of hypersensitivity to any components of the camrelizumab, apatinib and Capecitabine formulation, or other antibody formulation. Patients who may receive live vaccine during the study, or previous had vaccination within 4 weeks. Known or occurrence of central nervous system (CNS) metastases or hepatic encephalopathy. Peripheral neuropathy> Grade 1. Patients with any active autoimmune disease or history of autoimmune disease. History of immunodeficiency or human immunodeficiency virus (HIV) infection. Clinically significant cardiovascular and cerebrovascular diseases, including but not limited to severe acute myocardial infarction within 6 months before enrollment, unstable or severe angina, or coronary artery bypass surgery, Congestive heart failure (New York heart association (NYHA) class > 2), ventricular arrhythmia which need medical intervention. Hypertension and unable to be controlled within normal level following treatment of anti-hypertension agents (within 3 months): systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg. Coagulation abnormalities (INR>1.5 or APTT>1.5×ULN), with bleeding tendency or are receiving thrombolytic or anticoagulant therapy. History of hereditary or acquired bleeding and thrombotic tendency, such as hemophilia, coagulopathy, thrombocytopenia, hypersplenism, etc. Patients with obvious cough blood or hemoptysis volume of half teaspoon (2.5 ml) or more within 2 months before entering the study. Have significant clinically significant bleeding symptoms or have a clear bleeding tendency within 3 months before entering the study, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, fecal occult blood++ and above at baseline, or vasculitis, etc. Previous Arterial/venous thrombosis events within 6 months. Required for long-term anticoagulant therapy with warfarin or heparin, or long-term antiplatelet therapy (aspirin ≥300 mg/day or clopidogrel ≥75 mg/day). Severe infection within 4 weeks before the first medication (e.g. need for intravenous antibiotics, antifungal or antiviral drugs), or active infection or an unexplained fever > 38.5°C during screening visits or on the first scheduled day of dosing. Participated in any other drug clinical study within 4 weeks before the first administration, or no more than 5 half lives from the last administration. Known history of psychotropic drug abuse or drug abuse. Pregnant and lactating women. Any other medical, psychiatric, or social condition deemed by the investigator to be likely to interfere with a subject's rights, safety, welfare, or ability to sign informed consent, cooperate, and participate in the study or would interfere with the interpretation of the results.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Camrelizumab combined with Apatinib and Capecitabine<br>Camrelizumab was administered 200mg iv every 3 weeks. Capecitabine was administered 1000mg/m2 orally, b.i.d. every 3 weeks (Day 1-14 of a treatment cycle) Apatinib:A safety-run-in was conducted in the first cycle to identify the recommended dose of Apatinib, the initial dose was administered 250mg orally daily every 3 weeks (Day 1-14 of a treatment cycle). The dose of Apatinib increase and reduction was 250 mg orally q.d. and 250 mg orally q.o.d. every 3 weeks respectively according to the number of doses limiting toxicity events (DLTs) in the initial group. The final dose of Apatinib for the extension stage was detemained by the result of safety-run-in stage. | Drug: Camrelizumab<br>* Camrelizumab was administered 200mg iv every 3 weeks.<br>Drug: apatinib<br>* Apatinib A safety-run-in was conducted in the first cycle to identify the recommended dose of Apatinib, the initial dose was administered 250mg orally daily every 3 weeks (Day 1-14 of a treatment cycle) The dose of Apatinib increase and reduction was 250 mg orally q.d. and 250 mg orally q.o.d. every 3 weeks respectively according to the number of doses limiting toxicity events (DLTs) in the initial group. The final dose of Apatinib for the extension stage was detemained by the result of safety-run-in stage.<br>Drug: Capecitabine<br>* Capecitabine was administered 1000mg/m2 orally, b.i.d. every 3 weeks (Day 1-14 of a treatment cycle)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | The proportion of patients with measurable disease who achieved complete response (CR) or partial response (PR) | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rates (DCR) | The proportion of patients achieving CR or PR or stable disease (SD) | 30 months | 
| Progression-Free Survival | The duration from the beginning of the treatment to the disease progression, or death from any cause, or last progression-free survival assessment for patients alive without progression | 30 months | 
| Overall Survival | The duration from the enrollment to death from any cause | 30 months | 
| Safety | The incidence of any grade treatment-related adverse events. | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Capecitabine, Targeted Molecular Therapy, Biliary Tract Cancer