Everolimus in Treating Patients With Previously Treated Unresectable or Metastatic Esophageal Cancer or Stomach Cancer

Study Overview
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Brief Summary
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RATIONALE: Everolimus 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 everolimus works in treating patients with previously treated unresectable or metastatic esophageal cancer or stomach cancer.

Detailed Description
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OBJECTIVES: Primary To determine the overall disease-control rate (complete response, partial response, or stable disease) in patients with previously treated unresectable or metastatic adenocarcinoma of the upper gastrointestinal tract treated with everolimus. Secondary To determine the safety and toxicity of everolimus in these patients. To determine the efficacy of everolimus, in terms of time to response, duration of response, time to tumor progression, progression-free survival, and overall survival, in these patients. To explore potential correlations between clinical outcome and biomarkers of interest, including S6 protein overexpression and/or other mTOR-related proteins in blood and tumor biopsy samples from these patients. OUTLINE: This is a multicenter study. Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood, serum, and tumor tissue samples are collected for biomarker analysis. After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months thereafter.

Official Title
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A Phase II Study of the mTOR Inhibitor RAD001 in Previously Treated Patients With Unresectable or Metastatic Adenocarcinoma of the Esophagus and Stomach

Conditions
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Esophageal Cancer, Gastric Cancer

Intervention / Treatment
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* Drug: everolimus
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of adenocarcinoma of the upper gastrointestinal tract Metastatic or unresectable disease Received 1-2 prior chemotherapy or biological therapy regimens for unresectable or metastatic disease Measurable disease in ≥ 1 dimension by CT scan or MRI Patients whose only measurable lesion is a metastatic lymph node are eligible provided they have permission from the principal investigator ECOG performance status 0-1 Life expectancy > 3 months ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN (≤ 5.0 times ULN if there is liver metastasis) Creatinine clearance > 60 mL/min Fasting serum cholesterol < 300 mg/dL or < 7.75 mmol/L* Fasting triglycerides < 2.5 times ULN* INR ≤ 3.5 (for patients on warfarin) Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 4 months after completion of study treatment (oral, implantable, or injectable contraceptives are not considered effective contraception for this study) More than 30 days since prior chemotherapy, surgery, radiotherapy, or investigational agents Exclusion Criteria: uncontrolled diabetes mellitus, defined as fasting serum glucose > 1.5 times ULN severely impaired lung function known HV infection active, bleeding diathesis unstable angina pectoris, symptomatic congestive heart failure, or myocardial infarction within the past 6 months serious uncontrolled cardiac arrhythmia active or uncontrolled infection requiring parenteral antimicrobials known liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent hepatitis) inability to swallow, impaired gastrointestinal (GI) function, or GI disease (e.g., ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) that would significantly alter the absorption of study drugs or preclude the use of oral medications other malignancy within the past 5 years except for nonmelanoma skin cancer or cervical carcinoma in situ known hypersensitivity to everolimus, sirolimus, or temsirolimus or to their excipients other medical conditions that, in the opinion of the investigator, would preclude study participation prior mTOR inhibitors (e.g., rapamycin, CCI-779) concurrent chronic treatment with steroids or another immunosuppressive agent concurrent prophylactic use of hematopoietic growth factors concurrent anticancer agents or therapy (including radiotherapy) other concurrent experimental agents concurrent strong inhibitors or inducers of the isoenzyme CYP3A4

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: Everolimus<br>Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity | Drug: everolimus<br> <br> Other: laboratory biomarker analysis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Disease-control Rate in Patients With Previously Treated Unresectable or Metastatic Adenocarcinoma of the Upper Gastrointestinal Tract Treated With Everolimus. | Disease control rate (DCR), defined as complete response (CR) + partial response (PR) + stable disease (SD) according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. | Radiologic disease assessment was performed every 8 weeks (14 days = 1 cycle) treatment discontinuation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival (OS), defined as the time from date of initial treatment to date of death. Survival function was estimated using the Kaplan-Meier method. | 2.5 year | 
| Efficacy in Terms of Progression Free Response | Progression-free survival (PFS), was defined as the time from the date of initial treatment to first objective documentation of disease progression, or death. Estimated using the Kaplan-Meier method. Complete response (CR) + partial response (PR) + stable disease (SD) were determined according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Radiologic disease assessments were utilized. | evry 3 months in year 1, every 6 months after that | 
| Observed Biomarkers | Potential correlations between clinical outcome and biomarkers of interest, including S6 protein overexpression and/or other mTOR-related proteins in tumor tissue samples from these patients. | 30 months | 
| Biomarker Correlations: Progression Free Survival | Potential correlations between progression free survival and S6 protein and mTOR-related proteins in tumor tissue samples from these patients. | 30 months | 
| Biomarker Correlations: Time to Progression | Potential correlations between time to progression and S6 protein and mTOR-related proteins in tumor tissue samples from these patients. | 30 months | 

 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 stomach, recurrent esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer, recurrent gastric cancer, stage III gastric cancer, stage IV gastric cancer