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Everolimus (RAD001) for the Treatment of Malignant Pleural Mesothelioma With Merlin/NF2 Loss as a Biomarker to Predict Sensitivity

Published: December 2, 2009

Primary Outcome Measures:

  • To determine the rate of clinical benefit (i.e. rate of complete or partial response plus stable disease) at 16 weeks for patients with malignant mesothelioma treated with everolimus as second or third line therapy. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

  • To determine the response rate, time to progression and overall survival for patients with mesothelioma treated with everolimus. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • To determine the toxicities of everolimus in this patient population. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • To explore whether or not Merlin/NF2 loss can be used as a biomarker to predict sensitivity to everolimus. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • To determine the relationship between response to treatment and the levels of soluble mesothelin-related peptide (SMRP) and osteopontin. [ Time Frame: 2 years ] [ Designated as safety issue: No ]


Inclusion Criteria:
  • Patients must have a histologically confirmed diagnosis of epithelioid, sarcomatoid, or mixed-type malignant pleural 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 (including chemotherapy, radiation therapy, antibody-based therapy, etc.)
  • 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 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.
  • 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
  • Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
  • Severely impaired lung function as evidenced by:
    • Spirometry and/or DLCO that is ≤ 50% 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.
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