Everolimus (RAD001) for the Treatment of Malignant Pleural Mesothelioma With Merlin/NF2 Loss as a Biomarker to Predict Sensitivity
Condition: Malignant Pleural Mesothelioma
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Intervention: everolimus
Intervention description: Everolimus will be administered at a dose of 10mg orally once daily continuously. Dose reduction may be required depending on the type and severity of toxicity encountered. One cycle will be considered 28 days. Patients will have CT scans to evaluate for response after cycle 1 and cycle 2, and then every two cycles thereafter.
Intervention MeSH terms: Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: mesothelioma; pleural; RAD001; Everolimus; 09-142; thoracic; lung; epithelioid; sarcomatoid

Summary:

      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.
    

Eligibility criteria:

        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.