Citations 1
Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia
Karp, Judith E. , Vener, Tatiana, Raponi, Mitch , Ritchie, Ellen K. , Gore, Steven D. , Morris, Lawrence E. , Feldman, Eric J. , Greer, Jacqueline M., Malek, Sami N. , Ironside, Valerie, Galkin, Steven, McDevitt, Michael A. , Roboz, G., Gocke, Christopher D. , Derecho, Carlo, Palma, John F. , Wright, John J., Garret-Mayer, Elizabeth, Smith, Benjamin D. , Carraway, Hetty E. , Levis, Mark J. , Roboz, Gail J. , Wang, Yixin , Kaufmann, Scott H. , Wright, John J.
Blood | October 15, 2011 | Volume: 119 | Issue: 1 | Pages: 55-63
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.