Gemcitabine and Cisplatin Plus Sorafenib in Patients With Advanced Biliary Tract Carcinomas Naive to Systemic Therapy

Study Overview
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Brief Summary
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The purpose of this study is to test an investigational combination of drugs for bile duct or gallbladder cancers. Gemcitabine and cisplatin are two forms of chemotherapy commonly used in combination to treat bile duct and gallbladder cancers. We are looking to improve treatment results. We will attempt to do so by adding sorafenib (a type of monoclonal antibody) to your treatment plan. Sorafenib acts by attaching to blocking specific targets on cells. These targets may help the cancer cells grow and divide. This study will help answer the question of whether sorafenib is a helpful drug in patients with bile duct or gallbladder cancers when given with gemcitabine and cisplatin. This study is a phase 2 study. The purpose of a phase 2 study is to find out what effects, good and/or bad, sorafenib in combination with gemcitabine and cisplatin has on advanced bile duct and gallbladder cancers.

Official Title
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A Phase II Study of Gemcitabine and Cisplatin Plus Sorafenib in Patients With Advanced Biliary Tract Carcinomas Naïve to Systemic Therapy

Conditions
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Extrahepatic Bile Duct Cancer, Gallbladder Cancer

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically / cytologically verified, non-resectable, recurrent, or metastatic biliary tract carcinoma including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma. Combined cholangiocarcinoma and hepatocellular carcinoma is allowed.Patients must have uni-dimensionally measurable disease by x-ray, CT scan, MRI scan or physical examination. KPS ≥ 80% Age ≥ 18 years Adequate bone marrow function defined as: Hb ≥ 8 g/dl, ANC ≥ 1.5 K/mcL, Platelets ≥ 100 K/mcL Adequate renal function defined as Serum creatinine < 2.0 mg/dl and calculated creatinine clearance ≥ 60 ml/min using the formula: Cockcroft-Gault formula: Cockcroft-Gault Formula - MALES CrCl = (140 - age[years]) (body wt[kg]) (72) (serum creatinine [mg/dL]) Cockcroft-Gault Formula - FEMALES CrCl = 0.85 x male value If calculated creatinine clearance is not within range using the above formula, then measured levels from 24-hour urine collection may be used to calculate the creatinine clearance. Adequate hepatic function defined as total bilirubin ≤ 2 mg/dl, ALT/AST/ ≤ 3 x ULN (≤ 5 if liver metastases). Patients with biliary obstruction can join if bilirubin corrects to required limit after adequate biliary drainage. PT/INR ≤ 1.7 and PTT ≤ 1.5 x ULN, unless the patient is receiving anti-coagulation therapy with agents such as warfarin or heparin Patients who have received prior local therapy, i.e. embolization, radiation therapy, etc. (except for chemoembolization) are eligible provided that measurable disease falls outside the treatment field or within the field but has shown an increase of ≥20% in the size. Prior local therapy must be completed at least 4 weeks prior to the baseline scan Women of childbearing potential must have a negative pregnancy test. Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter. Patients are encouraged to continue barrier method contraception for two years or longer after treatment. Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Any previous chemotherapy, biologic therapy, or investigational agent, except for 5-FU or gemcitabine given as adjuvant therapy as single agents and/or as radio-sensitizing agents. Patient must have completed adjuvant therapy no less than six months prior to accrual. Patients with previous significant allergic hypersensitivity to gemcitabine are excluded. Evidence of another active cancer that may influence patient outcome as determined by the Principal Investigator, except for non-melanoma skin carcinoma, melanoma in-situ, in-situ carcinoma of the cervix curatively treated, treated superficial bladder cancer, and adenocarcinoma of the prostate that has been surgically treated with a post-treatment PSA that is non-detectable. Known brain metastases History of primary central nervous system tumors or brain metastases, and/or seizures not well controlled with standard medical therapy. Uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements. Known HIV positive patient Blood Pressure of > 150/100 mm Hg Significant cardiovascular disease including congestive heart failure (New York Heart Association Class II or higher) or active angina pectoris. History of a myocardial infarction within 6 months. History of a stroke or transient ischemic attack within 6 months. Clinically significant peripheral vascular disease. Evidence of bleeding diathesis or coagulopathy. Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks. Uncontrolled infection. Known or suspected allergy to sorafenib or any agent given in the course of this trial. Pregnant (positive pregnancy test) Breast-feeding should be discontinued if the mother is to be treated on clinical trial. Serious non-healing wound, ulcer, or bone fracture Use of St. John's Wort or rifampin (rifampicin) Any condition that impairs patient's ability to swallow whole pills Any malabsorption problem

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: Gemcitabine and Cisplatin plus Sorafenib<br>This is a non-randomized, open label, single institution, phase II study of gemcitabine and cisplatin plus sorafenib for the treatment of patients with advanced or biliary tract carcinomas naïve to systemic therapy. | Drug: Gemcitabine<br>* Gemcitabine: 800 mg/m^2 over 30 minutes IV, weekly for 2 weeks, followed by a week off treatment.<br>Drug: Cisplatin<br>* 20 mg /m^2 over 30 minutes IV, weekly for 2 weeks, followed by a week off treatment.<br>Drug: Sorafenib<br>* 400 mg PO once a day continuously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | Progression free survival will be calculated from study entry to documented disease progression, death from any cause, or drop out due to toxicity, whichever occurs first. | 6 months | 
| Median PFS | Progression free survival will be calculated from study entry to documented disease progression, death from any cause, or drop out due to toxicity, whichever occurs first. | 6 mos | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GALL BLADDER, BILE DUCTS, BAY 43-9006, SORAFENIB, CISPLATIN, GEMCITABINE, 09-029