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

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.

Figures

Figure 1

OS for all 63 patients treated with the T + E arm A. Dotted lines indicate 95% CI.

Figure 2

OS by response category for 62 patients treated in arm A. Responders: CR (complete remission) PR/HI (partial remission/hematologic improvement. Nonresponders: SD + PD indicates stable disease plus progressive disease.

Figure 3

DFS (median, 6; 95% CI, 5.1, Infinity) for the 15 arm A patients who achieved CR. Dotted lines indicate 95% CI.

Figure 4

Accuracy of the optimized quantitative PCR assay in a phase 2 study of T + E study in elderly AML. (A) ROC analysis using complete remission (CR) only as response. AUC indicates area under the ROC curve. (B) A 2 × 2 contingency table using the optimal cutoff and 2-gene assay performance characteristics. NR indicates no response; PPV, positive predictive value; NPV, negative predictive value; ORR, overall response rate; Spec, specificity; and Sens, sensitivity. (C) Kaplan-Meier analysis of patients stratified using an optimal ratio cut-off of 5.2. HR indicates hazard ratio.

Figure 5

OS of 41 AML patients treated with intensive induction chemotherapy with Ara-C, anthracycline, and a third agent (flavopiridol or etoposide): stratification by high versus low 2-gene ratio. Median ratio = 0.959. HR indicates hazard ratio.