1. Translational phase I trial of vorinostat (suberoylanilide hydroxamic acid) combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia.
- Author
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Gojo I, Tan M, Fang HB, Sadowska M, Lapidus R, Baer MR, Carrier F, Beumer JH, Anyang BN, Srivastava RK, Espinoza-Delgado I, and Ross DD
- Subjects
- ATP Binding Cassette Transporter, Subfamily B genetics, ATP Binding Cassette Transporter, Subfamily B metabolism, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters metabolism, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cytarabine administration & dosage, Etoposide administration & dosage, Female, Gene Expression Regulation, Leukemic drug effects, Humans, Hydroxamic Acids administration & dosage, Karyotype, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Recurrence, Translational Research, Biomedical, Treatment Outcome, Tumor Necrosis Factor Decoy Receptors genetics, Tumor Necrosis Factor Decoy Receptors metabolism, Vorinostat, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: To determine the maximum-tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine (ara-C or cytosine arabinoside) 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 one to seven at three escalating dose levels: 200 mg twice a day, 200 mg three times a day, and 300 mg twice a day. On days 11 to 14, etoposide (100 mg/m(2)) and cytarabine (1 or 2 g/m(2) twice a day if ≥65 or <65 years old, respectively) were given. The study used a standard 3+3 dose escalation design., Results: Eighteen of 21 patients with acute myelogenous leukemia (AML) treated on study completed planned therapy. Dose-limiting toxicities [hyperbilirubinemia/septic death (1) and anorexia/fatigue (1)] were encountered at the 200 mg three times a day level; thus, the MTD was established to be vorinostat 200 mg twice a day. Of 21 patients enrolled, seven attained a complete remission (CR) or CR with incomplete platelet recovery, including six of 13 patients treated at the MTD. The median remission duration was seven months. No differences in percentage 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 twice a day can be given safely for seven days before treatment with cytarabine and etoposide. The relatively high CR rate seen at the MTD in this poor-risk group of patients with AML warrants further studies to confirm these findings., (©2013 AACR.)
- Published
- 2013
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