Everolimus and Combination Chemotherapy in Treating Patients With Metastatic Stomach or Esophageal Cancer

OBJECTIVES:

I. To determine the maximum tolerated dose of everolimus to use in combination with mFOLFOX6
[oxaliplatin, leucovorin (leucovorin calcium), 5-FU (fluorouracil)].

II. To better describe the toxicities associated with the combination of everolimus with
mFOLFOX6.

III. To assess response rate and progression-free survival in this patient population.

IV. To assess overall survival in patients with metastatic gastric, esophageal and
gastroesophageal junction (GEJ) adenocarcinoma treated with the combination of mFOLFOX6 +
everolimus.

OUTLINE: This is a dose-escalation study of everolimus. Patients receive fluorouracil
intravenously (IV) continuously over 46 hours, leucovorin calcium IV over 2 hours, and
oxaliplatin IV over 2 hours on day 1. Patients also receive oral everolimus once daily on
days 1-28. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 1 year.

Inclusion Criteria:

- Patients must have histologically confirmed diagnosis of gastric, esophageal, and GEJ
adenocarcinoma

- Patients must have metastatic disease

- Patients must not have received any chemotherapy for metastatic disease

- Patients may have received prior adjuvant chemotherapy; completion of chemotherapy
must be greater than 6 months from date of recurrent disease

- Patients must have computed tomography (CT) or magnetic resonance imaging (MRI) scan;
patients must have at least one measurable site of disease according to Response
Evaluation Criteria in Solid Tumors (RECIST) criteria that has not been previously
irradiated; if the patient has had previous radiation to the marker lesion(s), there
must be evidence of progression since the radiation

- Patients must have a ECOG Performance Status of 0-1

- Absolute neutrophil count (ANC) > 1,500/mcl

- Platelet count > 100,000/mcl

- Hemoglobin (Hg) > 9 g/dL

- Serum creatinine < 1.5 mg/dl and/or Creatinine clearance > 60 cc/min

- Bilirubin < 1.5 mg/dl

- Serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamic pyruvic
transaminase (SGPT) =< 2.5 x institutional upper limit of normal (IULN) (=< 5 x upper
limit of normal [ULN] in patients with liver metastases)

- Fasting serum cholesterol =< 300 mg/dL or =< 7.75 mmol/L

- Fasting triglycerides =< 2.5 x ULN; NOTE: in case one or both of these thresholds are
exceeded, the patient can only be included after initiation of appropriate lipid
lowering medication

- Patients should have controlled diabetes as evidenced by hemoglobin (Hb)A1C =< 8%

- International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5;
(anticoagulation is allowed if target INR =< 1.5 on a stable dose of warfarin or on a
stable dose of low molecular weight [LMW] heparin for > 2 weeks at time of
randomization)

- Due to the possibility of harm to a fetus or nursing infant from this treatment
regimen, patients must not be pregnant or nursing (or plan to become pregnant); women
and men of reproductive potential must have agreed to use a highly effective
contraceptive method for at least 8 weeks after treatment

- Patients with risk factors for contraction hepatitis B or C should undergo screening
prior to treatment on protocol. Patients with detectable viral titers are required to
receive treatment for 4 weeks prior to starting protocol therapy.

- Patients must be able to swallow pills

- No other prior malignancy within the past 3 years 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

- All patients 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

- Patients must have pathology specimen available for submission

Exclusion Criteria:

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of study drug (including chemotherapy,
radiation therapy, antibody based therapy, etc)

- Patients who have received prior treatment with an mammalian target of rapamycin
(mTOR) inhibitor (sirolimus, temsirolimus, everolimus)

- Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus,
temsirolimus) or to its excipients

- Patients, who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the study

- Prior treatment with any investigational drug within the preceding 4 weeks

- Patients receiving chronic, systemic treatment with corticosteroids (prednisone > 10
mg per day) or another immunosuppressive agent; topical or inhaled corticosteroids
are allowed

- Patients should not receive immunization with attenuated live vaccines within one
week of study entry or during study period

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York heart Association Class III or
IV

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- Severely impaired lung function as defined as spirometry and diffusion lung
capacity of carbon monoxide (DLCO) that is 50% of the normal predicted value
and/or 02 saturation that is 88% or less at rest on room air

- Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN

- Active (acute or chronic) or uncontrolled severe infections

- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis

- A known history of human immunodeficiency virus (HIV) seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection)

- Patients with an active, bleeding diathesis; history of noncompliance to medical
regimens

- Patients unwilling to or unable to comply with the protocol