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

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.

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