The goal of this clinical research study is to find the highest safe dose of RAD001 that can be given as a treatment for leukemia, mantle cell lymphoma, or myelofibrosis. Another goal is to learn how effective the dose that is found is as a treatment. RAD001 is a new drug that was designed to block proteins that are important in the development and growth of cancer.

RAD001 (Everolimus), an ester of the macrocytic immunosuppressive agent sirolimus (rapamycin, Rapamune™), is an orally administered cell cycle inhibitor with antitumor properties. RAD001 is approved in Europe as an immunosuppressive agent in patients who have received a prior solid organ transplant. RAD001 specifically inhibits the mammalian target of rapamycin (mTOR), a Ser/Thr kinase involved in the initiation of mRNA translation. RAD001 inhibits the growth of a wide range of histologically diverse tumor cells. RAD001 is being developed as a cytostatic agent to delay the time to tumor recurrence/progression or to increase survival in patients with various malignancies. Key features of this compound include its good tolerability, unique mechanism of action, ability to arrest cells in the G1 phase, and ability to induce apoptosis. As mTOR-related messengers, particularly PI3K, AKT, p70S6K kinase and 4E-BP1, are known to be both constitutively activated in the hematologic malignancies and to mitigate against the activity of current anti-leukemia therapy, RAD001 is an important agent to study in these disorders.

Objectives:

Primary: To establish the safety and activity of RAD001 in patients with advanced, relapsed or refractory acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, chronic myeloid leukemia in blastic-phase, agnogenic myeloid metaplasia (myelofibrosis), chronic lymphocytic leukemia, T-cell leukemia, and mantle cell lymphoma.

Secondary:

1. To establish survival, time to progression, time to treatment failure, duration of response, in patients on study.
2. To conduct laboratory studies relating the investigational agent RAD001 to its cellular targets including analyses of p70S6K and 4E-BP1, effect of RAD001 in leukemia cells with altered mitochondrial respiration, and sequential assays of activity of AKT/mTOR and AKT/ßcatenin pathways.

• Leukemia
• Mantle Cell Lymphoma
• Myelofibrosis

Inclusion Criteria:

1. Patients with advanced, relapsed, or refractory: acute leukemias (AML, ALL), MDS, CMML in transformation with ³ 10% peripheral blood/bone marrow blasts, CML-BP, AMM, CLL, T-cell leukemia, or mantle cell lymphoma.
2. Serum bilirubin less than or equal 2 mg/dL, SGOT or SGPT < 3 X upper limit of normal, serum creatinine less then or equal 2 mg/dL, unless considered due to organ leukemic involvement or Gilbert’s syndrome
3. The effects of RAD001 on the developing human fetus are unknown. For this reason and because inhibitors of mRNA translation are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
4. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients who have had cytotoxic chemotherapy (other than hydroxyurea or corticosteroids) or radiotherapy within 7 days prior to entering the study.
2. Patients may not be receiving any other cytotoxic investigational agents.
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to RAD001. RAD001 must not be administered to patients with known hypersensitivity to everolimus, sirolimus or to any of its excipients. Excipients include butylated hydroxytoluene, magnesium stearate, hydroxypropylmethyl-cellulose, crospovidone, and lactose.
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
5. Pregnant women are excluded from this study because RAD001 has a potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with RAD001, breastfeeding should be discontinued if the mother is treated with RAD001.