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

• Published in: Clinical cancer research Vol. 12; no. 17; pp. 5165 - 5173
• Main Authors: Yee, Karen W L, Zeng, Zhihong, Konopleva, Marina, Verstovsek, Srdan, Ravandi, Farhad, Ferrajoli, Alessandra, Thomas, Deborah, Wierda, William, Apostolidou, Efrosyni, Albitar, Maher, O'Brien, Susan, Andreeff, Michael, Giles, Francis J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2006
• Subjects: 4E-BP1; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Administration, Oral; Adolescent; Adult; Aged; Antineoplastic agents; Biological and medical sciences; chronic lymphocytic leukemia; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Everolimus; Female; Humans; hypoxia-inducible factor; 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; Medical sciences; Middle Aged; mTOR inhibitor; myelodysplastic syndrome; Myelodysplastic Syndromes - drug therapy; p70S6K; Pharmacology. Drug treatments; 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; Human; Protein kinase mTOR; Relapse; Treatment resistance; Treatment; Phase II trial; Phase I trial; Lactone; Malignant hemopathy; Protein synthesis inhibitor; Macrolide; Everolimus
• ISSN: 1078-0432; 1557-3265
• 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.