PMID- 16951235
OWN - NLM
STAT- MEDLINE
DCOM- 20071130
LR  - 20220317
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 12
IP  - 17
DP  - 2006 Sep 1
TI  - Phase I/II study of the mammalian target of rapamycin inhibitor everolimus 
      (RAD001) in patients with relapsed or refractory hematologic malignancies.
PG  - 5165-73
AB  - 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.
FAU - Yee, Karen W L
AU  - Yee KW
AD  - Authors' Affiliations: Departments of Leukemia and Blood and Marrow 
      Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
FAU - Zeng, Zhihong
AU  - Zeng Z
FAU - Konopleva, Marina
AU  - Konopleva M
FAU - Verstovsek, Srdan
AU  - Verstovsek S
FAU - Ravandi, Farhad
AU  - Ravandi F
FAU - Ferrajoli, Alessandra
AU  - Ferrajoli A
FAU - Thomas, Deborah
AU  - Thomas D
FAU - Wierda, William
AU  - Wierda W
FAU - Apostolidou, Efrosyni
AU  - Apostolidou E
FAU - Albitar, Maher
AU  - Albitar M
FAU - O'Brien, Susan
AU  - O'Brien S
FAU - Andreeff, Michael
AU  - Andreeff M
FAU - Giles, Francis J
AU  - Giles FJ
LA  - eng
GR  - P01 CA55164/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/antagonists & inhibitors
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Cell Cycle Proteins
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Drug-Related Side Effects and Adverse Reactions
MH  - Everolimus
MH  - Female
MH  - Humans
MH  - Killer Cells, Natural/immunology
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy
MH  - Leukemia, Myeloid, Acute/*drug therapy
MH  - Leukemia, Prolymphocytic/*drug therapy
MH  - Leukemia, T-Cell/*drug therapy
MH  - Lymphoma, Mantle-Cell/*drug therapy
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Myelodysplastic Syndromes/*drug therapy
MH  - Phosphoproteins/antagonists & inhibitors
MH  - Phosphorylation
MH  - Protein Kinases/drug effects/metabolism
MH  - Recurrence
MH  - Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors
MH  - Signal Transduction/drug effects
MH  - Sirolimus/administration & dosage/adverse effects/*analogs & 
      derivatives/therapeutic use
MH  - T-Lymphocytes/immunology
MH  - TOR Serine-Threonine Kinases
MH  - Treatment Outcome
MH  - Vasculitis, Leukocytoclastic, Cutaneous/chemically induced
EDAT- 2006/09/05 09:00
MHDA- 2007/12/06 09:00
CRDT- 2006/09/05 09:00
PHST- 2006/09/05 09:00 [pubmed]
PHST- 2007/12/06 09:00 [medline]
PHST- 2006/09/05 09:00 [entrez]
AID - 12/17/5165 [pii]
AID - 10.1158/1078-0432.CCR-06-0764 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2006 Sep 1;12(17):5165-73. doi: 10.1158/1078-0432.CCR-06-0764.