slow accrual

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.

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.

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

Adverse events were measure during treatment which ranges from 5-196 days.

The trial was stopped early due to slow accrual. 18-33 patients were needed to address objectives, however only 7 patients were enrolled. Insufficient patients responded to the treatment to allow laboratory correlates with response to be analyzed.