Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia

摘要: 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 randomized 84 (age range, 70-90 years; median, 76 years) who were not candidates conventional chemotherapy. Arm A (T 600 mg twice day × 14 days, E 100 days 1-3 and 8-10) arm B 400 200 similar CR, but had greater toxicity. Total CR was 25%, 30 death rate 7%. 2-gene signature high RASGRP1 low aprataxin (APTX) expression previously predicted response. Assays using blasts from subset 40 patients treated this study showed that AMLs RASGRP1/APTX ratio more than 5.2 78% negative predictive value 87%. This did correlate outcome 41 chemotherapies. The next T-based clinical trials will test the ability to enrich responders prospectively. is registered at www.clinicaltrials.gov as #NCT00602771.