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


METHODS
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.
Yee
Karen W L
KW
Authors' Affiliations: Departments of Leukemia and Blood and Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Zeng
Zhihong
Z
Konopleva
Marina
M
Verstovsek
Srdan
S
Ravandi
Farhad
F
Ferrajoli
Alessandra
A
Thomas
Deborah
D
Wierda
William
W
Apostolidou
Efrosyni
E
Albitar
Maher
M
O'Brien
Susan
S
Andreeff
Michael
M
Giles
Francis J
FJ
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D000068338:Everolimus; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D015463:Leukemia, Prolymphocytic / Q000188:drug therapy*; D015458:Leukemia, T-Cell / Q000188:drug therapy*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D012008:Recurrence; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome; D018366:Vasculitis, Leukocytoclastic, Cutaneous / Q000139:chemically induced
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus