title: 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.
abstract: 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.
authors.affiliation: Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD 21231-1000, USA. jkarp2@jhmi.edu
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Karen
authors.initials: K
authors.lastname: Flatten
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Feldman
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Greer
authors.forename: David A
authors.initials: DA
authors.lastname: Loegering
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Ricklis
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Morris
authors.forename: Ellen
authors.initials: E
authors.lastname: Ritchie
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Valerie
authors.initials: V
authors.lastname: Ironside
authors.forename: Timothy
authors.initials: T
authors.lastname: Talbott
authors.forename: Gail
authors.initials: G
authors.lastname: Roboz
authors.forename: Son B
authors.initials: SB
authors.lastname: Le
authors.forename: Xue Wei
authors.initials: XW
authors.lastname: Meng
authors.forename: Paula A
authors.initials: PA
authors.lastname: Schneider
authors.forename: Nga T
authors.initials: NT
authors.lastname: Dai
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Levis
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000284:Administration, Oral; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D015363:Quinolones / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: D004791:Enzyme Inhibitors; D015363:Quinolones; D005047:Etoposide; D051231:Farnesyltranstransferase; C402769:tipifarnib