A Study of Combination of Gemcitabine, Oxaliplatin (GEMOX)-Sorafenib in Patients With Advanced Biliary Tract Cancer

Study Overview
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Brief Summary
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The purpose of this study is to build on the efficacy of the GEMOX regimen by adding Sorafenib in the treatment of Biliary Tract Cancer. Since there is no data on the combination of these three agents, the investigators plan to evaluate the safety in a run-in phase I portion in order to define the recommended phase II dose (RPTD). The phase II trial will enroll 40 patients at the RPTD level within 2 years in order to provide a preliminary estimate of progression-free survival (primary endpoint of the trial) in the target population.

Detailed Description
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The purpose of this study is to build on the efficacy of the GEMOX regimen by adding Sorafenib in the treatment of Biliary Tract Cancer. Since there are no data on the combination of these three agents, the investigators plan to evaluate the safety in a run-in phase I portion in order to define the recommended phase II dose (RPTD). The phase II trial will enroll 40 patients at the RPTD level within 2 years in order to provide a preliminary estimate of progression-free survival (primary endpoint of the trial) in the target population.

Official Title
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A Phase I/II Study of Combination of Gemcitabine, Oxaliplatin and Sorafenib (GEMOX-Sorafenib) in Patients With Advanced Biliary Tract Cancer

Conditions
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Cholangiocarcinoma, Biliary Tract Cancer, Gallbladder Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Histologically or cytologically confirmed biliary tract or gallbladder carcinoma Any stage of disease is allowed but the patients must not be candidates for curative resection Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 in Ph I ECOG performance status 0-2 in Ph II. Patients with ECOG PS of 2 will only be enrolled if they will comprise at most 25% of the total accruals. This will be monitored in real time to ensure that at any point during accrual, PS 2 patients will comprise <= 25% of the total accruals Patients must have normal organ and marrow function as defined below within 14 days of study entry: Absolute neutrophil count >= 1,500 cells/mm3 Platelet count >= 60,000/mm3 Creatinine < 1.5 upper limit of normal (ULN). Aspartate transaminase (AST) and Alanine transaminase (ALT) <= 2.5 x ULN. Bilirubin <= 3.0 mg/dl International normalized ratio (INR) < 1.5 or a prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin will not be candidates for the trial. Patients on anticoagulation with low molecular weight or heparinoids are protocol candidates. Any number of previous lines of chemotherapy is allowed for the phase I portion During the phase II trial, no prior chemotherapy for inoperable or metastatic disease is allowed except 5-FU or Capecitabine as radiosensitizers. Prior adjuvant chemotherapy is allowed. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib. Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures. Life expectancy of greater than 12 weeks Exclusion Criteria: Investigational agents within 28 days prior to Day 1 of study Chemotherapy within 4 weeks prior to Day 1 of study Nitrosoureas, mitomycin-C within 6 weeks prior to Day 1 of study. Prior treatment with sorafenib, gemcitabine or oxaliplatin Prior history of peripheral neuropathy > Grade 1 (e.g., diabetic neuropathy) Pregnant or breast-feeding female Patients with a history of allergic reactions or sensitivity attributed to compounds of similar chemical or biologic composition to sorafenib, oxaliplatin or gemcitabine Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis) Cardiac disease: Congestive heart failure > class II New York Heart Association (NYHA). Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management. Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis. Known human immunodeficiency virus (HIV) infection and Hepatitis B and Hepatitis C. Active clinically serious infection > CTCAE Grade 2. Arterial thrombotic/embolic events like myocardial infarct and cerebrovascular accident including transient ischemic attacks within the past 6 months. Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug. Serious non-healing wound, ulcer, or bone fracture. Evidence or history of bleeding diathesis or coagulopathy Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug. Use of St. John's Wort or rifampin (rifampicin). Any medical condition, which in the opinion of the investigator places the patient at an unacceptably high risk for toxicities

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: GEMOX + Sorafenib<br>Gemcitabine and Oxaliplatin (GEMOX) and Sorafenib. Gemcitabine: 1000 or 750 mg/m2, IV, Day 1 of each 14 day cycle, until progression or unacceptable toxicity develops. Oxaliplatin: 100 or 75 mg/m2, IV, Day 2 of each 14 day cycle, until progression or unacceptable toxicity develops. Sorafenib: 200 mg, Orally, twice daily for each 14-day cycle, until progression or unacceptable toxicity develops. | Drug: Gemcitabine<br>* Intravenously (IV) on Day 1 of each 14 day cycle, until progression or unacceptable toxicity develops.<br>* Other names: Gemzar;Drug: Oxaliplatin<br>* Intravenously (IV) on Day 2 of each 14 day cycle, until progression or unacceptable toxicity develops.<br>* Other names: Eloxatin;Drug: Sorafenib<br>* Orally, twice daily for each 14-day cycle, until progression or unacceptable toxicity develops.<br>* Other names: BAY 43-9006;|
| Experimental: Phase 2 - RPTD GEMOX + Sorafenib<br>Recommended Phase Two Dose (RPTD) of Gemcitabine and Oxaliplatin (GEMOX) and Sorafenib: Gemcitabine: Recommended Phase II Dose determined from Phase I, Day 1 of each 14 day cycle, until progression or unacceptable toxicity develops. Oxaliplatin: Recommended Phase II Dose determined from Phase I, Day 2 of each 14 day cycle, until progression or unacceptable toxicity develops. Sorafenib: Recommended Phase II Dose determined from Phase I, Orally, twice daily for each 14-day cycle, until progression or unacceptable toxicity develops. | Drug: Gemcitabine<br>* Intravenously (IV) on Day 1 of each 14 day cycle, until progression or unacceptable toxicity develops.<br>* Other names: Gemzar;Drug: Oxaliplatin<br>* Intravenously (IV) on Day 2 of each 14 day cycle, until progression or unacceptable toxicity develops.<br>* Other names: Eloxatin;Drug: Sorafenib<br>* Orally, twice daily for each 14-day cycle, until progression or unacceptable toxicity develops.<br>* Other names: BAY 43-9006;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Recommended Phase II Dose (RPTD) of the Combination of Sorafenib and GEMOX in Patients With Advanced Biliary Tract Cancer (BTC). | Establish the recommended phase II dose (RPTD) of the combination of sorafenib and GEMOX in patients with advanced biliary tract cancer (BTC). | First two 14-day Phase I cycles | 
| Phase II: Obtain an Estimate of the 9-month Progression-free Survival Rate in Patients With Advanced BTC Receiving the RPTD of the Combination Sorafenib and GEMOX. | Rate of study participants achieving progression-free survival at 9 months post-initiation of study therapy at RPTD. Progression-Free Survival (PFS) is defined as the time elapsed from the start of treatment to the date of documented progression or death, whichever comes first. For surviving patients without progression who begin alternative treatment, PFS will be censored at the last date of documented progression-free status prior to starting alternative treatment. Similarly, losses to follow up will be censored at the last date of documented progression-free status. | 9 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Estimate Overall Response Rate and Clinical Benefit Rate. | Overall response rate [CR + PR]. Clinical Benefit Rate [Complete Response (CR) + Partial Response (PR) + Stable Disease (SD)] per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). | About 9 Months | 
| Phase II: Estimate Overall Survival | Overall survival is defined as the time elapsed from the start of treatment until death. For surviving patients, follow-up will be censored at the date of last contact. | Start of treatment until death or date of last contact | 
| Phase II: Further Evaluate the Safety of the Proposed Combination | Rate of study participants experiencing toxicity after receiving study therapy at the recommended Phase 2 Dose (RPTD). | About 9 Months | 
| Phase II: Explore Biomarkers of Response to the Combination | A study of the correlation between biomarker levels and response to RPTD study therapy. Blood samples for biomarker analysis are collected at baseline and on day 1 of Cycles 2 onward | Baseline, Day 1 of Cycle 2 and subsequent cycles, about 9 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cholangiocarcinoma, Biliary Tract Cancer, Gallbladder Cancer