Clinical Cancer Research Molecular Diagnostics in Cancer Therapeutic Development: Fulfilling the Promise of Personalized Medicine Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yee, K. W.L.
Right arrow Articles by Giles, F. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yee, K. W.L.
Right arrow Articles by Giles, F. J.
Clinical Cancer Research Vol. 12, 5165-5173, September 1, 2006
© 2006 American Association for Cancer Research


Cancer Therapy: Clinical

Phase I/II Study of the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) in Patients with Relapsed or Refractory Hematologic Malignancies

Karen W.L. Yee1, Zhihong Zeng2, Marina Konopleva2, Srdan Verstovsek1, Farhad Ravandi1, Alessandra Ferrajoli1, Deborah Thomas1, William Wierda1, Efrosyni Apostolidou1, Maher Albitar1, Susan O'Brien1, Michael Andreeff1,2 and Francis J. Giles1

Authors' Affiliations: Departments of 1 Leukemia and 2 Blood and Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Francis J. Giles, Department of Leukemia, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030. Phone: 713-792-8217; Fax: 713-794-4297; E-mail: frankgiles{at}aol.com.

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.




This article has been cited by other articles:


Home page
Molecular Cancer TherapeuticsHome page
J. A. Garcia and D. Danielpour
Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies
Mol. Cancer Ther., June 1, 2008; 7(6): 1347 - 1354.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
H. M.W. Verheul, B. Salumbides, K. Van Erp, H. Hammers, D. Z. Qian, T. Sanni, P. Atadja, and R. Pili
Combination Strategy Targeting the Hypoxia Inducible Factor-1{alpha} with Mammalian Target of Rapamycin and Histone Deacetylase Inhibitors
Clin. Cancer Res., June 1, 2008; 14(11): 3589 - 3597.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
D. A. Rizzieri, E. Feldman, J. F. DiPersio, N. Gabrail, W. Stock, R. Strair, V. M. Rivera, M. Albitar, C. L. Bedrosian, and F. J. Giles
A Phase 2 Clinical Trial of Deforolimus (AP23573, MK-8669), a Novel Mammalian Target of Rapamycin Inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies
Clin. Cancer Res., May 1, 2008; 14(9): 2756 - 2762.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
S. Chumsri, W. Matsui, and A. M. Burger
Therapeutic Implications of Leukemic Stem Cell Pathways
Clin. Cancer Res., November 15, 2007; 13(22): 6549 - 6554.
[Abstract] [Full Text] [PDF]


Home page
JCOHome page
M. Fouladi, F. Laningham, J. Wu, M. A. O'Shaughnessy, K. Molina, A. Broniscer, S. L. Spunt, I. Luckett, C. F. Stewart, P. J. Houghton, et al.
Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors
J. Clin. Oncol., October 20, 2007; 25(30): 4806 - 4812.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
B. E. Johnson, D. Jackman, and P. A. Janne
Rationale for a Phase I Trial of Erlotinib and the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) for Patients with Relapsed Non Small Cell Lung Cancer
Clin. Cancer Res., August 1, 2007; 13(15): 4628s - 4631s.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
M. Y. Follo, S. Mongiorgi, C. Bosi, A. Cappellini, C. Finelli, F. Chiarini, V. Papa, M. Libra, G. Martinelli, L. Cocco, et al.
The Akt/Mammalian Target of Rapamycin Signal Transduction Pathway Is Activated in High-Risk Myelodysplastic Syndromes and Influences Cell Survival and Proliferation
Cancer Res., May 1, 2007; 67(9): 4287 - 4294.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
Z. Zeng, D. D. Sarbassov, I. J. Samudio, K. W. L. Yee, M. F. Munsell, C. Ellen Jackson, F. J. Giles, D. M. Sabatini, M. Andreeff, and M. Konopleva
Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML
Blood, April 15, 2007; 109(8): 3509 - 3512.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
F. J. Giles
Syk-driven mTOR in lymphoma-complimentary targets?
Blood, December 15, 2006; 108(13): 3957 - 3958.
[Full Text] [PDF]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 2006 by the American Association for Cancer Research.