Capecitabine With or Without Sunitinib Malate as First-Line Therapy in Treating Patients With Metastatic Cancer of the Esophagus or Gastroesophageal Junction

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sunitinib malate 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. It is not yet known whether capecitabine is more effective when given alone or together with sunitinib malate in treating patients with metastatic esophageal cancer or gastroesophageal junction cancer. PURPOSE: This randomized phase II trial is studying how well capecitabine works compared with capecitabine given together with sunitinib malate as first-line therapy in treating patients with metastatic cancer of the esophagus or gastroesophageal junction.

Detailed Description
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OBJECTIVES: Primary Compare the progression-free survival of elderly (age ≥ 65 years) and/or poor performance status patients with metastatic adenocarcinoma of the esophagus or gastroesophageal junction treated with capecitabine with verus without sunitinib malate. Report other indicators of efficacy with these regimens, including the confirmed response rate, overall survival, time to tumor progression, duration of response, and time to treatment failure. Compare the adverse event profiles of these regimens in these patients. Secondary Explore whether certain key proteins associated with anti-VEGF therapy are able to predict tumor response. Bank paraffin-embedded tissue blocks or slides, and blood products for future studies. OUTLINE: This is a multicenter study. Patients are stratified according to gender (male vs female), ECOG performance status (0 vs 1 vs 2), and age (≥ 65 years vs < 65 years). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral capecitabine twice daily on days 1-14. Patients experiencing disease progression may crossover to arm II at the physician's discretion. Arm II: Patients receive oral capecitabine as in arm 1 and oral sunitinib malate once daily on days 1-21. In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Tumor tissue samples are collected at baseline for evaluation of protein markers as possible predictors of tumor response to this regimen. Samples are analyzed by IHC for expression levels of markers After completion of study therapy, patients are followed periodically for 3 years.

Official Title
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A Randomized Phase II Trial of Sunitinib Plus Capecitabine Versus Capecitabine Alone (With the Potential for Crossover) for Elderly and/or Poor Performance Status Patients With Metastatic Adenocarcinoma of the Esophagus or Gastroesophageal Junction

Conditions
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Adenocarcinoma of the Gastroesophageal Junction, Esophageal Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: sunitinib malate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction Metastatic disease Unresectable disease with no curative options Measurable disease with ≥ 1 lesion whose longest diameter can be accurately measured as ≥ 2.0 cm by conventional techniques or ≥ 1.0 cm by spiral CT Not a candidate for a conventional multi-drug chemotherapy regimen with fairly standard dosing (i.e., patient is able to tolerate at least 80% of standard dosing) Patients who have been offered and declined conventional multi-drug chemotherapy are eligible No known CNS metastases PATIENT CHARACTERISTICS: ECOG performance status (PS) 0-2 and age ≥ 65 years OR PS 2 and age ≥ 18 years but < 65 years Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Total bilirubin normal Alkaline phosphatase ≤ 2 times upper limit of normal (ULN) Creatinine ≤ 1.5 times ULN Creatinine clearance ≥ 60mL/min AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Willing to provide tissue samples for central review and research purposes Able to swallow pills No immunocompromised patients (other than related to the use of corticosteroids), including patients known to be HIV-positive No co-morbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens No uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situations that would limit compliance with study requirements No NYHA class III or IV heart failure No uncontrolled hypertension except at the discretion of treating oncologist No other active malignancy except for nonmelanoma skin cancer or carcinoma in situ of the cervix No known dihydropyrimidine dehydrogenase deficiency (DPD) PRIOR CONCURRENT THERAPY: No prior chemotherapy, radiotherapy, immunotherapy, or biological therapy for recurrent or metastatic cancer Prior chemotherapy or radiotherapy are allowed if they had been administered as adjuvant or neoadjuvant therapy and a complete surgical resection of the original cancer had been achieved No prior sunitinib malate No prior radiotherapy to > 30% of the marrow cavity at any time More then 4 weeks since prior major surgery At least 12 days since prior and no concurrent CYP3A4 inducers, including rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's wort, efavirenz, and tipranavir At least 7 days since prior and no concurrent CYP3A4 inhibitors, including azole antifungals (ketoconazole, itraconazole), clarithromycin, erythromycin, diltiazem, verapamil, HIV protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfinavir), and delavirdine No other concurrent specific treatment (other than hormonal therapy) in patients with a history of prior malignancy

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral capecitabine twice daily on days 1-14. Patients experiencing disease progression may crossover to arm II at the physician's discretion. | Drug: capecitabine<br>* Given orally<br>|
| Experimental: Arm II<br>Patients receive oral capecitabine as in arm 1 and oral sunitinib malate once daily on days 1-21. | Drug: capecitabine<br>* Given orally<br>Drug: sunitinib malate<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Progression-free Survival | The primary analysis will be a comparison of Arm A to Arm B using a one-sided log-rank test between the 2 Kaplan-Meier curves. All patients meeting the eligibility criteria, who started treatment will be considered evaluable for the primary endpoint. If a patient is still alive 3 years after registration, no further follow-up is required. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete Response or Partial Response) | A confirmed tumor response is defined to be a CR or PR noted as the objective status on 2 consecutive evaluations ≥4 weeks apart. Confirmed tumor response will be evaluated using the first 6 cycles of treatment. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for response. The confirmed response rates between the 2 arms will be compared using a Chi-Square or Fisher's Exact test. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD. | Up to 3 years | 
| Overall Survival | Overall survival is defined as the time from randomization to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier. | Up to 3 years | 
| Time to Disease Progression | Time to disease progression is defined as the time from randomization to the earliest date documentation of disease progression occurs. If a patient dies without a documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death. The distribution of time-to-progression will be estimated using the method of Kaplan-Meier. | Up to 3 years | 
| Time to Treatment Failure | Time to treatment failure is defined to be the time from the date of randomization to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. | Up to 3 years | 
| Duration of Response | Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented. | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the esophagus, adenocarcinoma of the gastroesophageal junction, recurrent esophageal cancer, stage IV esophageal cancer, stage III esophageal cancer