title: Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia.
abstract: Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.
authors: Division of Hematologic Malignancies, John Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231-1000, USA. jkarp2@jhmi.edu
authors: Judith E
authors: JE
authors: Karp
authors: Tatiana I
authors: TI
authors: Vener
authors: Mitch
authors: M
authors: Raponi
authors: Ellen K
authors: EK
authors: Ritchie
authors: B Douglas
authors: BD
authors: Smith
authors: Steven D
authors: SD
authors: Gore
authors: Lawrence E
authors: LE
authors: Morris
authors: Eric J
authors: EJ
authors: Feldman
authors: Jacqueline M
authors: JM
authors: Greer
authors: Sami
authors: S
authors: Malek
authors: Hetty E
authors: HE
authors: Carraway
authors: Valerie
authors: V
authors: Ironside
authors: Steven
authors: S
authors: Galkin
authors: Mark J
authors: MJ
authors: Levis
authors: Michael A
authors: MA
authors: McDevitt
authors: Gail R
authors: GR
authors: Roboz
authors: Christopher D
authors: CD
authors: Gocke
authors: Carlo
authors: C
authors: Derecho
authors: John
authors: J
authors: Palma
authors: Yixin
authors: Y
authors: Wang
authors: Scott H
authors: SH
authors: Kaufmann
authors: John J
authors: JJ
authors: Wright
authors: Elizabeth
authors: E
authors: Garret-Mayer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D010597:Pharmacogenetics; D011379:Prognosis; D015363:Quinolones / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics; D012074:Remission Induction; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: C438188:APTX protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D015363:Quinolones; C491790:RASGRP1 protein, human; D012333:RNA, Messenger; D005047:Etoposide; C402769:tipifarnib