For patients with malignant pleural mesothelioma that has grown despite treatment with standard chemotherapy, no treatment has yet proven beneficial. The purpose of this study is to find out what effects, both good and bad, that everolimus has on the cancer. Everolimus works by blocking a protein that helps the cancer grow. The goal of this clinical research study is to learn if the study drug everolimus can shrink or slow the growth of mesothelioma. The safety of this drug will also be studied. The patients' physical state, changes in the size of the tumor, and laboratory findings taken during the study will help us decide if everolimus is safe and effective.

This is a multicenter, open label, phase II study of everolimus as a second or third line therapy for the treatment of advanced malignant pleural mesothelioma, which will also evaluate Merlin/NF2 loss as a biomarker to predict sensitivity to everolimus. Patients who have disease progression after one or two prior chemotherapy regimens will be eligible. In the first stage of this design, 19 patients will be accrued. If 6 or less patients among the first 19 patients show clinical benefit, then the study will be terminated and declared negative. If 7 or more patients show clinical benefit, than an additional 20 patients will be accrued to the second stage. At the end of the study, if 17 or more patients show clinical benefit out of a total of 39 patients enrolled, the regimen will be considered worthy of further investigation.

Inclusion Criteria:

• Patients must have a histologically confirmed diagnosis of epithelioid, sarcomatoid, or mixed-type malignant pleural or peritoneal mesothelioma that is not amenable to surgery.

• Patients must have measurable disease according to the modified RECIST criteria for mesothelioma.

• Patients must have adequate tissue sample available for analysis of NF2/Merlin loss. (archived tissue block or 10 unstained slides)

• Patients must have received no more than two prior systemic therapy regimens, and at least one of the regimens must have included pemetrexed.

• Patients must be at least 18 years of age.

• Karnofsky performance status > or = to 70%.

• Adequate renal function: serum creatinine ≤ 1.5 x ULN.

• Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND 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.

• Signed informed consent

• Patients must have adequate hepatic function as defined by:

  • AST and ALT ≤ 2.5 x ULN (≤ 5x ULN in patients with liver metastases)
  • Serum bilirubin ≤ 1.5 x ULN

• Patients must have adequate bone marrow function as defined by:

  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Platelets ≥ 100 x 109/L
  • Hemoglobin ≥ 9 g/dL

Exclusion Criteria:

• Patient has been previously treated with an mTOR inhibitor (sirolimus, temsirolimus, or everolimus).

• Patients currently receiving anticancer therapies or who have received anticancer therapies within 3 weeks of the start of study drug for chemotherapy, biologics, targeted therapies, or immunologics or 2 weeks for radiation provided that patients have recovered from all associated toxicities at the time of registration

• 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 (except with a dosage equivalent to ≤ prednisone 20 mg) or another immunosuppressive agent. Patients receiving corticosteroids must have been on a stable dosage regimen for a minimum of 4 weeks prior to the first planned treatment with everolimus. Topical or inhaled corticosteroids are allowed

• Patients should not receive immunization with attenuated live vaccines within one week of study entry.

• 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
  • uncontrolled diabetes as defined by fasting serum glucose > or = to 1.5 x ULN

• Severely impaired lung function as evidenced by:

  o DLCO < 35% of the normal predicted value and/or O2 saturation that is ≤ 88% at rest on room air

• A known history of 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

• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of everolimus)

• Patient has an active infection for which they received IV antibiotic, antiviral, or antifungal medications within 2 weeks of starting study drug.

• Patients with a "currently active" second malignancy.