Sunitinib in Treating Patients With Relapsed or Refractory Esophageal or Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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RATIONALE: Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well sunitinib works in treating patients with relapsed or refractory esophageal or gastroesophageal junction cancer.

Detailed Description
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OBJECTIVES: Primary To determine the progression-free survival rate (complete response, partial response, and stable disease as defined by RECIST criteria [Response Evaluation Criteria in solid Tumors]) at 24 weeks in patients with relapsed or refractory esophageal or gastroesophageal junction cancer treated with sunitinib malate. Secondary To explore the predictive role of a hybrid imaging protocol that combines PET/CT (Positron emission tomography) scan simultaneously with dynamic contrast-enhanced MRI. Correlate quantitative changes in mean vessel density, alterations in tumor cell proliferation, and apoptosis in tumor biopsy specimens with clinical outcome in these patients. To evaluate the objective response as defined by RECIST criteria, median overall survival, and median progression-free survival of these patients. To evaluate the toxicities of sunitinib malate in these patients. OUTLINE: Patients receive oral sunitinib malate once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and tumor tissue sample collection periodically for correlative laboratory studies. Tumor tissue samples are assessed by immunohistochemistry and TUNEL for detection and quantitation of mean vessel density, proliferating tumor cells, and apoptosis. Tumor tissue samples are also assessed by immunohistochemistry for MAPK levels. Blood samples are analyzed by ELISA for VEGF, PlGF, sVEGFR2, and sVEGFR3 levels. Patients also undergo PET/CT scan and dynamic contrast-enhanced MRI periodically for correlative studies. After completion of study treatment, patients are followed for at least 6 months.

Official Title
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A Mechanistic Radiographic and Biologic Phase 2 Single Agent Study of Sunitinib Malate in Relapsed/Refractory Esophageal and Gastroesophageal Cancers

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: sunitinib malate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed esophageal or gastroesophageal junction carcinoma that is not amenable to curative surgery or other curative therapy Advanced, relapsed or refractory disease Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques or as ≥ 10 mm by spiral CT scan No known brain metastases PATIENT CHARACTERISTICS: ECOG (Eastern Cooperative Oncology Group) performance status 0-1 Life expectancy > 12 weeks WBC ≥ 3,000/μL Absolute neutrophil count ≥ 1,500/μL Platelet count ≥ 100,000/μL Serum calcium ≤ 12.0 mg/dL Total bilirubin normal AST (aspartate aminotransferase) and ALT (Alanine Aminotransferase) ≤ 2.5 times upper limit of normal Creatinine normal OR creatinine clearance ≥ 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception prior to, during, and for 28 days after completion of study treatment No history of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib malate No ongoing cardiac dysrhythmias ≥ grade 2, atrial fibrillation of any grade, or prolongation of the QTc (corrected QT interval) interval to > 450 msec (for males) or > 470 msec (for females) No hypertension that cannot be controlled by medications (i.e., systolic/diastolic blood pressure > 150/100 mm Hg despite optimal medical therapy) No myocardial infarction, cardiac arrhythmia, stable/unstable angina, symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or stenting within the past 12 months No cerebrovascular accident or transient ischemic attack within the past 12 months No pulmonary embolism within the past 12 months No condition that would impair the ability to swallow and retain sunitinib malate tablets (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days No serious or nonhealing wound, ulcer, or bone fracture No pre-existing thyroid abnormality that cannot be maintained in the normal range with medication No concurrent uncontrolled illness including, but not limited to, ongoing or active infection or psychiatric illness/social situation that would limit compliance with study requirements PRIOR CONCURRENT THERAPY: Recovered from prior therapy At least 4 weeks since prior radiotherapy or major surgery At least 4 weeks since prior chemotherapy (6 weeks for mitomycin C, carmustine, or alkylating agents) No more than 6 prior courses of an alkylating agent No more than 450 mg/m² of prior doxorubicin hydrochloride or 900 mg/m² of prior epirubicin hydrochloride No more than 2 lines of prior therapy in the metastatic setting No prior anti-VEGF monoclonal antibodies, such as bevacizumab or aflibercept No prior tyrosine kinase inhibitors with similar targets (e.g., sorafenib tosylate or axitinib) No other concurrent investigational agents No concurrent therapeutic doses of coumarin-derivative anticoagulants, such as warfarin Warfarin at doses of ≤ 2 mg daily are allowed for prophylaxis of thrombosis Low molecular weight heparin allowed provided PT/INR (Prothrombin time and international normalized ratio) is ≤ 1.5 No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent agents with proarrhythmic potential (e.g., terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, and flecainide)

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: Sunitinib<br>Sunitinib 37.5 mg daily for a 4 week cycle | Drug: sunitinib malate<br>* Sunitinib 37.5 mg daily for a 4 week cycle<br>* Other names: SU011248;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Rate | Complete response, partial response, and stable disease) as assessed by RECIST criteria at 24 weeks | up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | The Overall Response Rate (ORR) was assessed using Partial Response + Complete Response for patients. Response and progression was evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. | up to 4 years | 
| Median Overall Survival Time | The median overall survival time will be reported using the 95% confidence intervals for the parameters. | up to 4 years | 
| Median Progression-free Survival Time | Progression free survival was measured as the time from start of treatment to the first measurement of tumor growth. | up to 4 years | 
| Frequency and Severity of Adverse Events | The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was utilized for adverse event reporting. | up to 4 years | 
| Change in Mean Vessel Density | Quantitative assessment of proliferating tumor cells, and apoptosis, of the laboratory and radiographic correlates, the analyses will be purely explorative. | up to 4 years | 
| Quantitative Assessment of Proliferating Tumor Cells and Apoptosis | Biopsy sample taken from patients before and after treatment Apoptosis measures using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, which measures 3' nicked DNA. DNA is degraded in the early steps of apoptosis into low molecular weight (LMW) fragments and the production of single strand breaks in the high molecular weight DNA.Both of these features of apoptosis can be detected by labeling free 3'-OH termini with modified nucleotides, in our case this will be biotin-labeled dUTP. Terminal deoxynucleotidyl transferase (TdT) is an enzyme that labels blunt-ends of DNA breaks and can catalyze polymerization of nucleotides to free 3'-OH DNA ends in a template-independent manner. The newly incorporated nucleotides are detected by a secondary antibody, avidin-peroxidase. After substrate reaction, the stained cells can be detected and counted under a light microscope. Apoptotic cells will be fixed with formaldehyde which links LMW DNA | up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent esophageal cancer, stage IIIA esophageal cancer, stage IIIB esophageal cancer, stage IIIC esophageal cancer, stage IV esophageal cancer