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

Abstract

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.

• Authors: Karen W L Yee, Zhihong Zeng, Marina Konopleva, Srdan Verstovsek, Farhad Ravandi, Alessandra Ferrajoli, Deborah Thomas, William Wierda, Efrosyni Apostolidou, Maher Albitar, Susan O'Brien, Michael Andreeff, Francis J Giles
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 17 Pg. 5165-73 (Sep 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16951235 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, metabolism)
• Recurrence
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
• T-Lymphocytes (immunology)
• TOR Serine-Threonine Kinases
• Treatment Outcome
• Vasculitis, Leukocytoclastic, Cutaneous (chemically induced)