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. ArmA(T 600 mg twice a day x 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day x 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.
Original language | English (US) |
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Pages (from-to) | 55-63 |
Number of pages | 9 |
Journal | Blood |
Volume | 119 |
Issue number | 1 |
DOIs | |
State | Published - Jan 5 2012 |
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology