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

Clin Cancer Res. 2006 Sep 1;12(17):5165-73. doi: 10.1158/1078-0432.CCR-06-0764.


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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Cell Cycle Proteins
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug-Related Side Effects and Adverse Reactions
  • Everolimus
  • Female
  • Humans
  • Killer Cells, Natural / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Prolymphocytic / drug therapy*
  • Leukemia, T-Cell / drug therapy*
  • Lymphoma, Mantle-Cell / drug therapy*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Myelodysplastic Syndromes / drug therapy*
  • Phosphoproteins / antagonists & inhibitors
  • Phosphorylation
  • Protein Kinases / drug effects
  • Protein Kinases / metabolism
  • Recurrence
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Sirolimus / analogs & derivatives*
  • Sirolimus / therapeutic use
  • T-Lymphocytes / immunology
  • TOR Serine-Threonine Kinases
  • Treatment Outcome
  • Vasculitis, Leukocytoclastic, Cutaneous / chemically induced


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Phosphoproteins
  • Everolimus
  • Protein Kinases
  • MTOR protein, human
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • Sirolimus