Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies.

PURPOSE Everolimus (RAD001, Novartis), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR), which regulates many aspects of cell growth and division. A phase I/II study was done to determine safety and efficacy of everolimus in patients with relapsed or refractory hematologic malignancies. EXPERIMENTAL DESIGN Two dose levels (5 and 10 mg orally once daily continuously) were evaluated in the phase I portion of this study to determine the maximum tolerated dose of everolimus to be used in the phase II study. RESULTS Twenty-seven patients (9 acute myelogenous leukemia, 5 myelodysplastic syndrome, 6 B-chronic lymphocytic leukemia, 4 mantle cell lymphoma, 1 myelofibrosis, 1 natural killer cell/T-cell leukemia, and 1 T-cell prolymphocytic leukemia) received everolimus. No dose-limiting toxicities were observed. Grade 3 potentially drug-related toxicities included hyperglycemia (22%), hypophosphatemia (7%), fatigue (7%), anorexia (4%), and diarrhea (4%). One patient developed a cutaneous leukocytoclastic vasculitis requiring a skin graft. One patient with refractory anemia with excess blasts achieved a major platelet response of over 3-month duration. A second patient with refractory anemia with excess blasts showed a minor platelet response of 25-day duration. Phosphorylation of downstream targets of mTOR, eukaryotic initiation factor 4E-binding protein 1, and/or, p70 S6 kinase, was inhibited in six of nine patient samples, including those from the patient with a major platelet response. CONCLUSIONS Everolimus is well tolerated at a daily dose of 10 mg daily and may have activity in patients with myelodysplastic syndrome. Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway are warranted.