A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2

Abstract

Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination.

Experimental design: Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design.

Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m(2) (30-minute loading infusion) followed by 20 mg/m(2) (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21(CIP1) induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent.

Conclusions: Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules.

Figure 1

Western blot analysis of protein expression of p21^CIP1, Mcl-1, and p-RNA Pol II in bone marrow samples containing ≥ 59% blasts obtained from patients, before and 24 h after alvocidib treatment. Patient samples are divided into 2 groups according to the 2 alvocidib infusion schemes (DSI and WLMI) employed in this study. GAPDH is used as an internal loading control. The panel below provides a color scheme comparing results for the pre-treatment sample to results for the post-treatment sample. Red = down-regulation, green = up-regulation, and white = no change.

Figure 2

Analysis of expression of p21^CIP1, Mcl-1, and p-RNA Pol II in U937 cells treated with 1-μM vorinostat in the presence of 90% patient human plasma collected before and 24 h after alvocidib treatment. Samples are divided into 2 groups according to the 2 alvocidib infusion schemes used in this study i.e., (A) DSI and (B) WLMI. As a control, results of an in vitro experiment with U937 cells treated (24 h) with vorinostat (1 μM) and/or alvocidib (150 nM) are also shown. GAPDH is used as an internal loading control. The panel below represents a color scheme comparing results for the pre-treatment sample to results for the post-treatment sample. Red = down-regulation, green = up-regulation, and white = no change.