Multi-institutional Phase II clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia
Mené sur 84 patients atteints d'une leucémie myélogène aiguë (âge médian : 76 ans), cet essai de phase II évalue l'activité et la toxicité du tipifarnib en combinaison avec l'étoposide
Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a Phase I trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized Phase II trial in 84 adults (age 70-90, median 76) who were not candidates for conventional chemotherapy. Arms A (T 600 mg BID x 14 days, E 100 mg days 1-3 and 8-10) and B (T 400 mg BID x 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A two-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+E on this study showed that AMLs with a RASGRP1:APTX ratio of > 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 two-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.