Translational phase I trial of vorinostat combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia
Mené sur 21 patients atteints d'une leucémie myéloïde aiguë récidivante ou réfractaire, cet essai de phase I évalue la dose maximale tolérée du vorinostat, un inhibiteur d'histone désacétylase, avant un traitement combinant cytarabine et étoposide
PURPOSE. To determine the maximum tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine and etoposide in patients with poor-risk or advanced acute leukemia; to obtain preliminary efficacy data, describe pharmacokinetics and in vivo pharmacodynamic effects of vorinostat in leukemia blasts. EXPERIMENTAL DESIGN. In this open-label phase I study vorinostat was given orally on days 1-7 at 3 escalating dose levels: 200 mg BID, 200 mg TID, and 300 mg BID. On days 11-14 etoposide (100 mg/m2) and cytarabine (1 or 2 g/m2 BID if ≥65 or <65 years old, respectively) were given. The study used a standard 3+3 dose escalation design. RESULTS. Eighteen of 21 AML patients treated on study completed planned therapy. Dose-limiting toxicities (hyperbilirubinemia/septic death [1] and anorexia/fatigue [1]) were encountered at the 200 mg TID level; thus the MTD was established to be vorinostat 200 mg BID. Of 21 patients enrolled, 7 attained a complete remission (CR) or CR with incomplete platelet recovery, including 6 of 13 patients treated at the MTD. The median remission duration was 7 months. No differences in % S-phase cells or multidrug resistance transporter (MDR1 or BCRP) expression or function were observed in vivo in leukemia blasts upon vorinostat treatment. CONCLUSIONS. Vorinostat 200 mg BID can be given safely for 7 days prior to treatment with cytarabine and etoposide. The relatively high CR rate seen at the MTD in this poor-risk group of AML patients warrants further studies to confirm these findings.