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

Judith E. Karp, Tatiana I. Vener, Mitch Raponi, Ellen K. Ritchie, B. Douglas Smith, Steven D. Gore, Lawrence E. Morris, Eric J. Feldman, Jacqueline M. Greer, Sami Malek, Hetty E. Carraway, Valerie Ironside, Steven Galkin, Mark J. Levis, Michael A. McDevitt, Gail R. Roboz, Christopher D. Gocke, Carlo Derecho, John Palma, Yixin WangScott H. Kaufmann, John J. Wright, Elizabeth Garret-Mayer

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 languageEnglish (US)
Pages (from-to)55-63
Number of pages9
JournalBlood
Volume119
Issue number1
DOIs
StatePublished - Jan 5 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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