Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This randomized phase II trial studies how well trametinib or combination chemotherapy works in treating patients with refractory or advanced biliary or gallbladder cancer or that cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving trametinib is more effective than combination chemotherapy in treating patients with biliary or gallbladder cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess overall survival (OS) in patients with refractory advanced biliary cancer randomized to Arm 1: trametinib compared to those randomized to Arm 2: chemotherapy (either 5-fluorouracil [fluorouracil] and leucovorin [leucovorin calcium] or capecitabine). SECONDARY OBJECTIVES: I. To determine the frequency and severity of adverse events of trametinib in this patient population. II. To assess response rate (RR) and progression-free survival (PFS) in patients randomized to Arm 1: trametinib and patients randomized to Arm 2: chemotherapy (fluorouracil [5-FU] or capecitabine in this patient population). TERTIARY OBJECTIVES: I. To determine if a 16-gene expression signature is predictive of mitogen-activated protein kinase kinase (MEK) efficacy as evidenced by improved RR, PFS, and OS. II. To evaluate the effects of trametinib on the inflammatory cytokine and explore potential associations with response rate and survival. III. To estimate lean soft tissue and fat mass weight gain as a result of treatment with trametinib vs. capecitabine in patients with advanced refractory biliary cancer. IV. To bank tissue samples for other future correlative studies including next generation sequencing and whole genome methylation assays. NOTE: These potential future correlative studies will not be performed until an amended protocol with relevant detailed information including specific arms and assays is approved by Cancer Therapy Evaluation Program (CTEP). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive trametinib orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive 1 of 2 treatment regimens at the discretion of the investigator. ARM IIA: Patients receive leucovorin calcium intravenously (IV) over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM IIB: Patients receive capecitabine PO twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years.

Official Title
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Randomized Phase II Trial of Single Agent MEK Inhibitor Trametinib (GSK1120212) Vs 5-Fluorouracil or Capecitabine in Refractory Advanced Biliary Cancer

Conditions
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Adult Cholangiocarcinoma, Advanced Adult Hepatocellular Carcinoma, BCLC Stage C Adult Hepatocellular Carcinoma, BCLC Stage D Adult Hepatocellular Carcinoma, Hilar Cholangiocarcinoma, Localized Non-Resectable Adult Liver Carcinoma, Recurrent Adult Liver Carcinoma, Recurrent Childhood Liver Cancer, Recurrent Extrahepatic Bile Duct Carcinoma, Recurrent Gallbladder Carcinoma, Stage II Gallbladder Cancer, Stage III Childhood Hepatocellular Carcinoma, Stage IIIA Gallbladder Cancer, Stage IIIB Gallbladder Cancer, Stage IV Childhood Hepatocellular Carcinoma, Stage IV Distal Bile Duct Cancer, Stage IVA Gallbladder Cancer, Stage IVB Gallbladder Cancer, Unresectable Extrahepatic Bile Duct Carcinoma

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Fluorouracil
* Other: Laboratory Biomarker Analysis
* Drug: Leucovorin Calcium
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DISEASE RELATED CRITERIA Patients 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 Patients must have measurable disease; computed tomography (CT) scans or magnetic resonance imaging (MRI)s used to assess measurable disease must have been completed within 28 days prior to registration; CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) PRIOR/CONCURRENT THERAPY CRITERIA Patients must have completed any prior chemotherapy at least 21 days prior to registration and have recovered from any of the effects AND Patients must have experienced progression to no more than 1 prior regimen of systemic chemotherapy for advanced biliary cancer OR Patients who received adjuvant chemotherapy and had evidence of disease recurrence within 6 months of completion of the adjuvant treatment are also eligible; if patient received adjuvant treatment and had disease recurrence after 6 months, patients will only be eligible after failing one regimen of systemic chemotherapy used to treat the (unresectable or metastatic) disease recurrence Patients must not have been treated with prior MEK inhibitors; prior 5-FU or capecitabine treatment is allowed only if given as a radiosensitizer concurrently with radiation therapy at least 12 weeks prior to registration or if given as part of any adjuvant therapy regimen >= 12 months prior to study enrollment Patients must have no plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy or any other type of therapy (including herbal or natural supplements) for treatment of cancer while on this treatment protocol For patients who have received prior cryotherapy, radiation therapy, 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) CLINICAL/LABORATORY CRITERIA Patients must have a Zubrod performance status of 0-1 Absolute neutrophil count (ANC) > 1000/mcL Platelets > 100000/mcL Total bilirubin =< 2.0 x the institutional upper limit of normal limits (IULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 3 x IULN; if liver metastases are present, AST and ALT must be =< 5 x IULN If the patient has had decompression of the biliary tree within the last 14 days, stability of the bilirubin level needs to be confirmed with two measurements that are within 5 to 7 days of each other; (the second measurement must be obtained within 7 days prior to registration;) both the first and second measurement must be =< 2.0 x IULN; stability is defined as the second measurement being no more than one point higher than the first Patients must have adequate kidney function as evidenced by at least ONE of the following: Serum creatinine =< 1.5 x IULN within 28 days prior to registration Calculated creatinine clearance >= 50 ml/min for patients with creatinine level of 1.0-1.5 x IULN; the serum creatinine value used in the calculation must have been obtained within 28 days prior to registration Patients with known history or current evidence of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) are not eligible: History of RVO or RPED, or predisposing factors to RVO or RPED (e.g. such as uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as: Evidence of new optic disc cupping Evidence of new visual field defects Intraocular pressure > 21 mmHg NOTE: ophthalmic exam is required for all patients; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration Patients must have echocardiogram and left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) within 28 days prior to registration; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration Patients must not have uncontrolled or clinically significant cardiovascular disease including: myocardial infarction within past 6 months; uncontrolled angina within past 6 months; class II-IV New York Heart Association (NYHA) congestive heart failure; grade 3 cardiac valve dysfunction; cardiac arrhythmia not controlled by medication; history of stroke or transient ischemic attack within 6 months; history of arterial thrombotic event (ATE) of any type in the past 6 months; treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled with anti-hypertensive therapy; known intra-cardiac defibrillators; known cardiac metastases Patients must have an electrocardiogram (ECG) within 28 days prior to registration; patients must have corrected QT interval (QTc) =< 500 msec; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration Must be able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels Must not have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO) or other agents used in study Must not have active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible) Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 4 months after discontinuation of study drug; a woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years SPECIMEN SUBMISSION CRITERIA Patients must submit paraffin-embedded tissue and blood for banking within 28 days after registration; paraffin-embedded tissue from prior surgical resection or from a diagnostic biopsy is acceptable REGULATORY CRITERIA Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trametinib<br>Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Trametinib<br>* Given PO<br>* Other names: Mekinist;|
| Experimental: Chemotherapy<br>Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15 (courses repeat every 28 days); or B) capecitabine PO BID on days 1-14 (courses repeat every 21 days). Patients treated until disease progression or unacceptable toxicity. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact. | Up to 2 years from registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Adverse event reporting followed the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. | Up to 2 years | 
| Objective Response Rate | Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. | Up to 2 years from registration | 
| Progression-free Survival | From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact. | Up to 2 years from registration |