RAD001(Everolimus) in Treating Patients With Myelodysplastic Syndromes

Study Overview
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Brief Summary
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RATIONALE: RAD001(Everolimus) may stop the growth of cancer cells by blocking some of the enzymes needed for their growth and by blocking blood flow to the cancer. PURPOSE: This phase II trial is studying how well RAD001(everolimus) works in treating patients with myelodysplastic syndromes.

Detailed Description
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OBJECTIVES: Primary Determine the clinical activity (improvement in erythroid response and/or improvement in other cytopenias, bone marrow morphology/cytogenetics) of RAD001(everolimus) in patients with low or intermediate-1 risk myelodysplastic syndromes. Assess the toxicity of this drug in these patients. Secondary Examine laboratory correlates (S6K1 levels, angiogenesis pre- and post-treatment) and determine how these correlates correspond to dosing and clinical activity of RAD001(everolimus). Evaluate the presence of HLA-DR15 and cytotoxic T-cell populations in patients pre- and post-treatment and correlate this with response to treatment. Examine the incidence of the null GSTT-1 phenotype in myelodysplastic syndromes patients and correlate this with response to RAD001(everolimus). OUTLINE: Patients receive oral RAD001(everolimus) once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or relapse. Blood samples are collected periodically during study. Samples are analyzed for S6K1 activity, effector T cells by flow cytometry, GSTT-1 by PCR, and HLA-DR15 levels.

Official Title
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A Phase 2 Trial of RAD001(Everolimus) in Low and Intermediate-1 Risk Myelodysplastic Syndrome

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: everolimus
* Other: laboratory biomarker analysis
* Procedure: Bone marrow aspirate/biopsy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Low or intermediate-1 risk myelodysplastic syndromes by International Prognostic Scoring System (IPSS) criteria IPSS score < 1.5 Requiring transfusion of 2 units of red blood cells at least once a month (four weeks prior to accrual on study) High levels of endogenous epoetin alfa (i.e., > 200 mU/mL) Unlikely to respond to epoetin alfa, or has a documented clinical non-response to epoetin alfa (at a dose of ≥ 40,000 U weekly) or darbepoetin alfa (at a dose > 200 mcg every other week) (i.e., < 2 g/dL increase in hemoglobin and no decrease in transfusion requirements after at least 4 weeks of treatment) No chronic myelomonocytic leukemia PATIENT CHARACTERISTICS: ECOG Performance Status of 0-2 Liver enzymes (AST and ALT) and total bilirubin ≤ 2 times upper limit of normal Serum creatinine ≤ 2 times upper limits of normal No clinically significant anemia due to iron, B12, or folate deficiencies; autoimmune or hereditary hemolysis; or gastrointestinal bleeding Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other serious or poorly controlled medical condition that could be exacerbated by or complicate compliance with study therapy PRIOR CONCURRENT THERAPY: At least 4 weeks since prior treatment (including growth factors) No chronic use (> 2 weeks) of physiologic doses of a corticosteroid agent (dose equivalent to > 10 mg/day of prednisone) within 28 days of the first day of study drug No concurrent use of another investigational agent No concurrent therapy with any cytotoxic drugs, steroids, or growth factors

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RAD001 (everolimus)<br>RAD001 (everolimus) at 10mg/day with Bone marrow aspirate/biopsy and other laboratory biomarker analysis | Drug: everolimus<br>* Patients will receive monotherapy with RAD001(everolimus)for 21 days within the 28 day cycle.<br>* Other names: RAD001;Other: laboratory biomarker analysis<br>* Laboratory correlates (cytotoxic t cell populations, S6K1 levels, GSTT-1 mutations, and the presence or absence of HLA-DR15) will be assessed to see if any of these correlates correspond to response.<br>Procedure: Bone marrow aspirate/biopsy<br>* Bone marrow aspirate and biopsy with cytogenetics should be obtained within 4 weeks prior to starting drug and at week 33. A bone marrow aspirate and biopsy should also be obtained for patients going off study prior to week 33 (including cytogenetics). The percentage of blasts on the aspirate should be used to determine the IPSS score.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Either a Major or Minor Erythroid Response (Hemoglobin Change From Baseline Measure) | Major erythroid response: (1) For patients with a baseline hemoglobin less than 11 g/dL, a major erythroid response is defined as a > 2 g/dL increase in hemoglobin from baseline; or (2) 100% decrease in red blood cell transfusion requirements. Minor erythroid response: (1) For patients with baseline hemoglobin less than 11 g/dL, a minor erythroid response is defined as an increase in hemoglobin greater than 1 g/dL but less than 2 g/dL from baseline; or (2) > 50% decrease in red blood cell transfusion requirements. | 2 years of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose- and Non-dose-limiting Toxicities | Number of Dose- and Non-dose-limiting Toxicities at the end of cycle 1 associated with RAD001 (see AE/SAE section for details). | at end of one cycle (28 days) | 
| Number of Participants With Bone Marrow Morphology and Cytogenetics Pre- and Post-therapy | Number of Participants with change in bone marrow morphology and cytogenetics | at 2 years of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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de novo myelodysplastic syndromes, secondary myelodysplastic syndromes, previously treated myelodysplastic syndromes