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Blood, 14 May 2009, Vol. 113, No. 20, pp. 4841-4852. Prepublished online as a Blood First Edition Paper on December 24, 2008; DOI 10.1182/blood-2008-08-172726. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-08-172726v1 113/20/4841    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Karp, J. E. Articles by Kaufmann, S. H. Search for Related Content PubMed PubMed Citation Articles by Karp, J. E. Articles by Kaufmann, S. H. Related Collections Free Research Articles Myeloid Neoplasia Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide Judith E. Karp1, Karen Flatten2, Eric J. Feldman3, Jacqueline M. Greer1, David A. Loegering2, Rebecca M. Ricklis1, Lawrence E. Morris4, Ellen Ritchie3, B. Douglas Smith1, Valerie Ironside1, Timothy Talbott3, Gail Roboz3, Son B. Le2, Xue Wei Meng2, Paula A. Schneider2, Nga T. Dai2, Alex A. Adjei2, Steven D. Gore1, Mark J. Levis1, John J. Wright5, Elizabeth Garrett-Mayer6,*, and Scott H. Kaufmann2,* 1 Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD; 2 Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN; 3 Department of Hematology/Oncology, New York Presbyterian Hospital, Cornell Medical Center, New York; 4 Bone Marrow Transplant Group of Georgia, Atlanta; 5 Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and 6 Hollings Cancer Center, Medical University of South Carolina, Charleston The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853 [ClinicalTrials.gov] . CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Tipifarnib and etoposide for older AML patients: from bench to bedside Felicetto Ferrara Blood 2009 113: 4824-4825. [Full Text] [PDF] This article has been cited by other articles: F. Ferrara Tipifarnib and etoposide for older AML patients: from bench to bedside Blood, May 14, 2009; 113(20): 4824 - 4825. [Full Text] [PDF]

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